tag:blogger.com,1999:blog-8365863781321170602024-03-05T07:31:39.817-05:00Melanoma_MissionaryThis is Jim Breitfeller's journey into the Maze of Melanoma. Jim Breitfeller has gathered medical information for the patient and the caregiver.
As Lance Armstrong would say "Lets stand Up to Cancer"
Jim's Battle with the Beast July 2005 to present.jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.comBlogger730125tag:blogger.com,1999:blog-836586378132117060.post-6435375747558631882015-04-23T11:27:00.003-04:002015-04-23T11:33:57.826-04:00Combinatorial Therapy Will Revolutionize Cancer Therapy ...Just wait until ASCO 2015!!<br />
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<strong>Bristol-Myer Squibb Pharmaceutical Research Institute</strong> <br />
Attention: Elliott Sigal<br />
Route 206, Provinceline Road<br />
P.O. Box 4000<br />
Princeton, New Jersey 08543 U.S.A<span class="text_exposed_hide">...</span><br />
<span class="text_exposed_hide"></span><span class="text_exposed_show"><br /> <strong><span style="color: red;">Date: 3-10-2010</span></strong></span><br />
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<strong>Dear Dr. Sigal:</strong><br />
I want to thank you for responding to my emails over the last few months. I know I can be candid and straight to the point sometimes. By reopening the compassionate Drug Use (ipilimumab) you and your company gave the Melanoma Patients “The Last Chance of HOPE”. You don’t know how much this means to us. If we haven’t passed the “Lethal Tumor Burden” we still have a chance of survival. I believe you have done your company justice and showed your compassion. My faith in the Company’s Ethics has been restored.<br />
<br />
Now we need to prove to the world that this drug may be one of the most important discoveries in the last twenty years of Cancer. By taking the “Brakes off the Immune System” we can harness our own immune system to battle cancer. Granted we may have to use the drug in combinatorial therapy to rid the host of the cancer once and for all. I hope you and your company can collaborate together with all the major players in this exciting field of Oncology. See it took millions of years for our immune system to evolve, so why do we think that one drug can do it all. We need to approach the Beast arm to arm, to block all the pathways so it can’t escape. This can only be done by using one’s own immune system.<br />
<br />
Can you imagine working out a protocol that will vaccinate the patient with the patients own tumor–specific antigen? And Ipilimumab (Anti-CTLA-4 Blockade) is at the center of this revolutionary therapy/protocol. Please if you get a chance, listen to some of the lectures and symposiums from the like of Dr. James Allison, Dr. Jedd Wolchok, Dr. Antonio Ribas, Dr. Jeffery Weber, Dr Keith Flaherty and others. You will be amazed at their accomplishments in the clinical setting. But they need more. They need access to the entire drug arsenal that is available across companies. We now know that timing and dose concentration plays a major roll in setting up an immune response. There are feedback loops. It is like dominos. You have this elaborate step-up. It may take weeks to build. Once you set it in motion, the chips begin to fall. There are different pathways, cytokines, T-cells, receptors, etc that need to be taken into account get the right immune response. This immune response can only be generated if you have all the keys to unlock the response. We need yours and other Pharmaceuticals to work together for the good of the cancer patients. We need to take down all the red tape which also includes the FDA.<br />
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“Our Life depends on it.” <br />
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Thanks again.<br />
Sincerely,<br />
Jim Breitfeller</div>
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“It is not the strongest of the species that survives, nor the most intelligent, but the one most <br />
responsive to change.”<br />
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~Charles Darwin~
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Take Care,
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Jimmy B<br />
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<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com8tag:blogger.com,1999:blog-836586378132117060.post-37281584241461825932015-03-27T09:51:00.000-04:002015-03-27T09:52:36.360-04:00The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" may be due to an enzyme called IDO<b>The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" may be due to an enzyme called IDO
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiMXjznS7a3LR944hRzUjaYH1vqAnXlNNEnP5-WeDn2aZNcJYdqFVCZv1MwiZeJUaft2amt4L7Y8wArHHnJtT4gm7vB5uAriD6B8gR8fZI5721rg1sS422IsiJ5oAIQeCXrQcbWlOGmWuA/s1600/IDO+2014-05-07_9-41-33.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiMXjznS7a3LR944hRzUjaYH1vqAnXlNNEnP5-WeDn2aZNcJYdqFVCZv1MwiZeJUaft2amt4L7Y8wArHHnJtT4gm7vB5uAriD6B8gR8fZI5721rg1sS422IsiJ5oAIQeCXrQcbWlOGmWuA/s1600/IDO+2014-05-07_9-41-33.jpg" height="160" width="400" /></a></div>
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As I research why some patients respond to therapies i.e. vaccination and other immunotherapy and others don’t, I ask WHY? In my quest to get the answer or answers, I came across a paper called “Marked Differences in Human Melanoma Antigen-Specific T Cell Responsiveness after Vaccination Using a Functional Microarray”.<br />
<br />
<b>Daniel S. Chen1,2#, Yoav Soen3#, Tor B. Stuge4, Peter P. Lee4, Jeffrey S. Weber5, Patrick O. Brown2,3, Mark M. Davis2,6*
1 Department of Internal Medicine/Division of Oncology, Stanford University, Stanford, California, United States of America, 2 Howard Hughes Medical Institute, Stanford University, Stanford, California, United States of America, 3 Department of Biochemistry, Stanford University, Stanford, California, United States of America, 4 Department of Medicine, Stanford University, Stanford, California, United States of America, 5 Norris Cancer Center, University of Southern California, Los Angeles, California, United States of America, 6 Department of Microbiology and Immunology, Stanford University, Stanford, California, United States of America<i></i></b>
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<strong><span style="color: red;">This is what I was looking for</span></strong><span style="color: red;">!</span> It may hold the answer or could possibly point me in the right direction.
In the paper I came across a diagram that peaked my interest. It was a comparison between responders and non-responders. <br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTBfvTBgciaNGbdruh8AeKRAI0D7MgsVOoMZGoGn-XwSjEyOgEpazjuKXsaX6DDIWIHYiLUDB3df3zVmSeqXNre5q2cpQLHvonpM6hFyZ9rDvZfp9pSaNJ-Z4XbHHZbxYvkSQFGvpu3MI/s1600/IDO-1.jpg" imageanchor="1"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjTBfvTBgciaNGbdruh8AeKRAI0D7MgsVOoMZGoGn-XwSjEyOgEpazjuKXsaX6DDIWIHYiLUDB3df3zVmSeqXNre5q2cpQLHvonpM6hFyZ9rDvZfp9pSaNJ-Z4XbHHZbxYvkSQFGvpu3MI/s320/IDO-1.jpg" height="400" width="333" /></a>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjGm38xFPnkYSg77QXiNJeVtx28sWCCAKOEq2uRpwWSev1zulNTr2P0kCq1flwOiEVZDH6OHZDb9vvhMDxd5cRaZREtT4Hdp5Bhrv_4SYTWMSdxCDRuvX7RyESXG_oN0JG_ceVsNeLEQgk/s1600/IDO-2.png" imageanchor="1"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjGm38xFPnkYSg77QXiNJeVtx28sWCCAKOEq2uRpwWSev1zulNTr2P0kCq1flwOiEVZDH6OHZDb9vvhMDxd5cRaZREtT4Hdp5Bhrv_4SYTWMSdxCDRuvX7RyESXG_oN0JG_ceVsNeLEQgk/s320/IDO-2.png" /></a>
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<div class="MsoNormal" style="margin: 0in 0in 0pt; mso-layout-grid-align: none;">
<span style="mso-bidi-font-family: Dutch801BT-Roman;">We concluded from these studies
that IL-1 and perhaps IL-6 play a critical role in the differentiation and expansion
of Th17 cells.</span><b><span style="font-family: "Frutiger-Bold",sans-serif; font-size: 9pt; mso-bidi-font-family: Frutiger-Bold;"> Yoshihiro Miyahara et al</span></b></div>
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<b><span style="font-family: "Frutiger-Bold",sans-serif; font-size: 9pt; mso-bidi-font-family: Frutiger-Bold;"></span></b> </div>
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<span lang="EN" style="color: black; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN;">IL-6 controls Th17 immunity by inhibiting the conversion
of naive CD4</span><span class="mb1"><sup><span lang="EN" style="color: black; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><span style="font-family: Arial Unicode MS;">+</span></span></sup></span><span lang="EN" style="color: black; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN;"> T cells into Foxp3</span><span class="mb1"><sup><span lang="EN" style="color: black; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><span style="font-family: Arial Unicode MS;">+</span></span></sup></span><span lang="EN" style="color: black; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN;"> regulatory T cells.</span><span style="mso-bidi-font-family: Dutch801BT-Roman;"><o:p></o:p></span></div>
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Using in vitro and in vivo approaches, we determined<sup> </sup>that
under neutral conditions, simultaneous activation of Tregs<sup> </sup>and naive
CD4<sup>+</sup> conventional T cells in the presence of APCs<sup> </sup>resulted
in conversion of Tregs into IL-17–producing cells,<sup> </sup>and endogenous
IL-1β was mandatory in this process according to <em>Vassiliki A. Boussiotis </em><em><span style="font-style: normal; mso-bidi-font-style: italic;">et al. “</span></em><b style="mso-bidi-font-weight: normal;">IL-1β–Mediated Signals Preferentially Drive
Conversion of Regulatory T Cells but Not Conventional T Cells into
IL-17–Producing Cells”<o:p></o:p></b></div>
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<div class="MsoNormal" style="margin: 0in 0in 0pt;">
<b style="mso-bidi-font-weight: normal;">IL-6 protects CD4 T
cells from cell death but also inhibits the suppressive effect of T regs.<o:p></o:p></b></div>
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<div class="MsoNormal" style="margin: 0in 0in 0pt;">
“Thus, the addition of<sup> </sup>IL-6 to the tumor
microenvironment skews the balance toward<sup> </sup>Th17 cells in a murine
model of pancreatic cancer. The delayed<sup> </sup>tumor growth and improved
survival suggests that induction of<sup> </sup>Th17 in the tumor
microenvironment produces an antitumor effect.”<span class="MsoHyperlink"><u><span style="color: blue;"> </span></u></span><em>David
C. Linehan<span style="mso-spacerun: yes;"> </span>et al</em><o:p></o:p></div>
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<span style="font-family: "Arial",sans-serif; font-size: 10pt;"><em><span style="background-color: white;"><span style="color: red;">They were looking at the cytokines secreted after the vaccine was
given. When I saw what the cytokines were, I knew I was on the right track. These
cytokines help in the differentiation of the CD4+ T-cells. What a find!!<o:p></o:p></span></span></em></span></div>
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<strong>Naïve CD4 T cells in the presence of<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span>TGF-b
and IL-2 and others differentiate into Tregs.<o:p></o:p></strong></div>
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<strong>TGF-b accelerates the CTLA-4 expression by stimulated CD4+
CD25- T-cells<o:p></o:p></strong></div>
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<strong>TGF-b requires CTLA-4 early after T-cell activation to
induce FoxP expression generating CD4+ CD25+ Treg<span style="mso-spacerun: yes;"> </span>Regulatory cells.<o:p></o:p></strong></div>
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<strong>The Th-17 cells produce IL-17.</strong> <span lang="EN" style="mso-ansi-language: EN;"><span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="color: teal;">.IL-17
induces the production of many other cytokines (such as IL-6, G-CSF, GM-CSF, IL-1β,
TGF-β, TNF-α</span></ins></span>)<o:p></o:p></span></div>
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<o:p> </o:p><br />
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So what was the non-responder missing, IL-6.<span style="mso-spacerun: yes;"> </span>With the missing IL-6, they weren’t able to produce
Th-17 that secreted IL-17.</div>
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While TGF-β is a critical differentiation factor for Treg
cells, IL6 completely inhibits the generation of Treg cells induced by TGF-β.
Instead, IL6 and TGF-β together induce the differentiation of pathogenic Th17
cells. With IL-6 missing in the microenvironment, Treg Cells flourish.<o:p></o:p></div>
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If the CD4 + T cells differentiate into TH2 cells that
produce IL-4, the other cells inhibited to produce IL-6. IL-4 was found to
inhibit <span lang="EN" style="mso-ansi-language: EN;"><span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="color: teal;">TNF-α</span></ins></span> and <span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="color: teal;">IL-1β</span></ins></span> by activated monocytes almost
100 %. The Secretion of IL-6 was decreased by approximately 80 % in the
presences of IL-4 Cytokine. TE Velde et al 1990</span><o:p></o:p></div>
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<strong><span style="color: red;"><span style="mso-spacerun: yes;"> </span>They were missing
“The Danger Signal”.<o:p></o:p></span></strong></div>
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<h4 style="margin: 12pt 0in 3pt;">
<span style="mso-bidi-font-family: Arial;"><span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="font-size: large;"><span style="color: teal;">Friendly inflammation “The Danger Signal”<o:p></o:p></span></span></ins></span></span></h4>
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<span style="mso-bidi-font-family: Arial;"><span style="color: teal;"><span class="msoIns"><ins datetime="2010-09-19T08:43">Most of the time you have no notion of the
microbial life-and-death struggle being waged within your body. At other times,
though, you are acutely aware of the exact location of the battleground, thanks
to the unmistakable signs of inflammation — heat, pain, redness, and swelling.
Inflammation, the buildup of fluid and cells at the point of infection/cancer,
is put into motion by cytokines — proteins that are released into the blood by
the innate immune system when it encounters germs. Cytokines function like
police dispatchers. They signal there's a problem, which activates the immune
system's highway patrol force: the circulating lymphocytes of the adaptive
immune system. These lymphocytes cruise the highways of the blood vessels and
lymphatic system. In response to the chemical signal from the cytokines,
increased blood flow rushes these circulating cells to the trouble spot. </ins></span><o:p></o:p></span></span><br />
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<h4 style="margin: 12pt 0in 3pt;">
<span style="mso-bidi-font-family: Arial;"><span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="mso-spacerun: yes;"><span style="color: teal; font-size: large;"> </span></span><span style="color: teal; font-size: large;">“The </span></ins></span><span style="font-size: large;">CD8+
T-cell-mediated Immune Response to Eradicate the Tumors</span><span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="font-size: large;"><span style="color: teal;">”<o:p></o:p></span></span></ins></span></span></h4>
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<span style="mso-spacerun: yes;"> </span><span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="color: teal;">“Three major events must occur to induce CD8+ T
cell–mediated, tumor-protective immunity against syngeneic melanoma. First, the
T-cell receptor must be triggered by a (or multiple) self antigen–derived
peptide MHC class I complex . Therefore, this event depends entirely on
appropriate antigen presentation, which is most efficiently provided by mature
dendritic cells. Peripherally tolerant or “ignorant” self-reactive T-cell
clones, once properly activated, may serve as tumor-specific effector T cells
.Second, simultaneously with T-cell receptor triggering, a distinct second
costimulatory signal must be delivered, mediated by IL-2, B7-1, or B7-2, which
engage IL-2 receptors and CD28 on the surface of the T cell, respectively</span></ins></span>.<span class="msoIns"><ins datetime="2010-09-19T08:43"><span style="color: teal;"> A source of these cofactors for
effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release
critical amounts of IL-2, or by mature dendritic cells that display an
increased level of B7-1/B7-2 costimulatory molecules on their cell surfaces. </span><span style="color: teal;"><strong>Third, inflammatory cytokines, including
IL-1, </strong><span style="color: red;">IL-6</span><strong>, IL-12,</strong></span><strong><span style="color: navy;"> </span><span style="color: black;">IL-17</span><span style="color: teal;">
and IFN-γ provide a third signal that acts directly on T cells, referred to as
the “danger signal”. This signal was found to optimally activate TH1
differentiation and lead to clonal expansion of T cells</span></strong></ins></span><strong>.<o:p></o:p></strong></div>
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<o:p> </o:p><br />
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<strong><span style="color: red;">The responder was able to produce <span class="msoIns"><ins datetime="2010-09-19T08:43">inflammatory cytokines, including IL-1, IL-6,
IL-12,<span style="color: navy;"> </span><span style="color: black;"><span style="color: red;">IL-17</span></span>
and IFN-γ </ins></span>provides<span class="msoIns"><ins datetime="2010-09-19T08:43"> a third signal that acts directly on T cells,
referred to as the “danger signal”. This signal was found to optimally activate
TH1 differentiation and lead to clonal expansion of T cells</ins></span> and
invoke a robust immune response to the Melanoma Cancer.</span></strong> </div>
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<div class="MsoNormal" style="margin: 0in 0in 0pt;">
Conclusion:<span style="mso-spacerun: yes;"> </span>Based on
my observation, the cytokine that ties this “Danger Signal” to the immune
system is IL-6.<o:p></o:p></div>
<br />
<ul style="margin-top: 0in;" type="disc">
<li class="MsoNormal" style="margin: 0in 0in 0pt; mso-list: l0 level1 lfo1; tab-stops: list .5in;"><b style="mso-bidi-font-weight: normal;">IL-6 protects CD4 T cells from cell
death but also inhibits the suppressive effect of Tregs.<o:p></o:p></b></li>
<li class="MsoNormal" style="margin: 0in 0in 0pt; mso-list: l0 level1 lfo1; tab-stops: list .5in;"><b style="mso-bidi-font-weight: normal;"><span lang="EN" style="color: black; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN;">IL-6
controls Th17 immunity by inhibiting the conversion of naive CD4</span></b><span class="mb1"><b style="mso-bidi-font-weight: normal;"><sup><span lang="EN" style="color: black; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><span style="font-family: Arial Unicode MS;">+</span></span></sup></b></span><b style="mso-bidi-font-weight: normal;"><span lang="EN" style="color: black; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN;"> T
cells into Foxp3</span></b><span class="mb1"><b style="mso-bidi-font-weight: normal;"><sup><span lang="EN" style="color: black; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Times New Roman"; mso-fareast-font-family: "Times New Roman";"><span style="font-family: Arial Unicode MS;">+</span></span></sup></b></span><b style="mso-bidi-font-weight: normal;"><span lang="EN" style="color: black; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN;"> regulatory T cells.</span></b></li>
</ul>
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<strong><span style="color: red;"><span lang="EN" style="color: black; mso-ansi-language: EN;"><span style="color: red;">So
what is causing the lack of IL-6 in the non-responders? The IDO enzyme. This </span></span><span lang="EN" style="mso-ansi-language: EN;">enzyme catalyzes the degradation of the
essential amino acid L-tryptophan to N-formylkynurenine.<sup><a href="http://en.wikipedia.org/wiki/Indoleamine_2,3-dioxygenase#cite_note-3#cite_note-3"></a></sup><span style="color: black;"><o:p></o:p></span></span></span></strong></div>
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<div class="MsoNormal" style="margin: 0in 0in 0pt;">
<span lang="EN" style="color: black; mso-ansi-language: EN;">IDO enzyme
degrades tryptophan and through the GCN2 kinase pathway inhibits the
transcription of IL-6. Without the transcription of IL-6, the IL-6 cytokine
cannot be produced leading to the T-cell differentialtion toward the T
Regulatory cell instead of the TH17 phenotype.<o:p></o:p></span></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimvr-cldNwDe7reYM7dVOu-M1MS6c_dSvTTazMDA1tm-BGaGjWifL-JmsPfZBNKcopaka0DJhA62xDrniJGc1zB6KBW2DAc7a987igHmNWy9lZ2qdNTnADKPYDfGiNAeZyrRnFXfn73wo/s1600/IDO-8.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimvr-cldNwDe7reYM7dVOu-M1MS6c_dSvTTazMDA1tm-BGaGjWifL-JmsPfZBNKcopaka0DJhA62xDrniJGc1zB6KBW2DAc7a987igHmNWy9lZ2qdNTnADKPYDfGiNAeZyrRnFXfn73wo/s1600/IDO-8.png" height="320" width="153" /></a></div>
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<div class="MsoNormal" style="margin: 0in 0in 0pt;">
<span lang="EN" style="color: black; mso-ansi-language: EN;">My
guess is the tumor induced enzyme called IDO may the <b style="mso-bidi-font-weight: normal;">Missing Link</b> <b style="mso-bidi-font-weight: normal;">to intiating an
immune response</b>.</span><span style="color: black;">IDO produced by Tumor
cells significantly inhibited interleukin (IL-2) expression and proliferative
response in T-cells and increased apoptosis (death) of T-cells.</span><span style="color: #403838; font-family: "Lucida Sans Unicode",sans-serif; mso-ansi-language: EN;"> </span><b style="mso-bidi-font-weight: normal;"><span lang="EN" style="color: #403838; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";">Tryptophan depletion is known to halt cell cycle progression by triggering
the antiproliferative GCN2 pathway in lymphocytes</span><span style="color: black;">.<o:p></o:p></span></b></div>
<br />
<div class="MsoNormal" style="margin: 0in 0in 0pt;">
<span style="color: black;">Also, </span><span lang="EN" style="color: #403838; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";">IDO is upregulated in antigen-presenting dendritic cells (<em><span style="mso-bidi-font-family: "Lucida Sans Unicode";">DC</span></em>) by autocrine
IFN-γ released as a result of T<sub>reg</sub> cell–induced CTLA-4/B7-dependent
cell-cell signaling</span><span lang="EN" style="color: #403838; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";">.<o:p></o:p></span></div>
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<span style="color: red;"><strong><span lang="EN" style="color: #403838; font-family: "Lucida Sans Unicode",sans-serif; mso-ansi-language: EN;">It is well established that IDO expression
by APCs or tumors can inhibit immune responses.</span><span lang="EN" style="color: #403838; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";"><o:p></o:p></span></strong></span></div>
<span style="color: red;"><strong>
</strong></span><br />
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<span lang="EN" style="color: #403838; font-family: "Lucida Sans Unicode",sans-serif; mso-ansi-language: EN;"><span style="color: red;"><strong>Tryptophan depletion by IDO-expressing
tumors is a common mechanism of immune evasion inducing regulatory T cells and
inhibiting effector T cells.<o:p></o:p></strong></span></span></div>
<br />
<div class="MsoNormal" style="margin: 0in 0in 0pt;">
<span lang="EN" style="color: #403838; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";">So adding IDO inhibitor to a combinatorial therapy like Yervoy for melanoma
cancer should see a synergist response.<o:p></o:p></span></div>
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<span lang="EN" style="color: #403838; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";"><o:p> </o:p></span></div>
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<span lang="EN" style="color: #403838; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";"><o:p> </o:p></span></div>
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<span lang="EN" style="color: #403838; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN; mso-bidi-font-family: "Lucida Sans Unicode";"><o:p> </o:p></span></div>
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<div class="MsoNormal" style="margin: 0in 0in 0pt;">
<span lang="EN" style="color: black; font-family: "Verdana",sans-serif; font-size: 10pt; mso-ansi-language: EN;"><o:p> </o:p></span></div>
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<br />
Bristol Myer Squibb and Incyte Corporation are following this Science along <br />
Newlink.<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
<br />
<br />
Take Care,
<br />
<br />
Jimmy B
<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a></div>
</div>
jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com2tag:blogger.com,1999:blog-836586378132117060.post-56835015905589994112014-05-19T19:37:00.001-04:002014-05-19T19:37:52.373-04:00Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms<a href="http://www.jimmunol.org/content/180/4/2011.full.pdf+html">Plasticity of Macrophage Function during Tumor Progression: Regulation by Distinct Molecular Mechanisms</a><br /><br />
<br /><br />
<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”<br /><br />
<br /><br />
~Charles Darwin~<br /><br />
Take Care,<br /><br />
Jimmy B<br /><br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-84641008690579669972014-05-19T19:35:00.001-04:002014-05-19T19:35:53.147-04:00IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells<a href="http://intl.jimmunol.org/content/178/4/2018.full">IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells</a><br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”~Charles Darwin~Take Care,Jimmy B<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com2tag:blogger.com,1999:blog-836586378132117060.post-43355050190827956182014-05-01T17:07:00.001-04:002014-05-01T17:10:41.172-04:00Immunotherapy.. The Magic Bullet.. The Breakthrough Therapy.. the Paradigm Shift.. The FutureI wrote about this as the "Magic bullet" back in 2009.Great insight in where immunotherapy is heading in the future.<br />
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<object height="315" width="480"><param name="movie" value="//www.youtube.com/v/XGeqAEr1RnE?version=3&hl=en_US"></param>
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<embed src="//www.youtube.com/v/XGeqAEr1RnE?version=3&hl=en_US" type="application/x-shockwave-flash" width="480" height="315" allowscriptaccess="always" allowfullscreen="true"></embed></object><br />
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When you combine anti-CD47 therapy with checkpoint therapy (anti-PD1 and or anti-CTLA4/Yervoy), you involve the innate and the adoptive immune system to eradicate cancer (Melanoma)<br />
I would like to see combinatorial therapy with checkpoint inhibitors like yervoy/anti-CTLA-4 & anti-PD-1along with anti-CD47 to eliminate the "don't eat me" signal, so the macrophages can get involved with the tumor elimination.<br />
<br />
<a href="http://www.youtube.com/watch?v=XGeqAEr1RnE&feature=share">http://www.youtube.com/watch?v=XGeqAEr1RnE&feature=share</a><br />
<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
<br />
<br />
Take Care,
<br />
<br />
Jimmy B<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com1tag:blogger.com,1999:blog-836586378132117060.post-91266638414005291852013-05-15T18:55:00.000-04:002013-05-15T22:00:34.610-04:00Bristol melanoma drug combo marks new advance in immunotherapy..melanoma..Jim Breitfeller<br />
<a name='more'></a><br />
<br />
<br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Reuters</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">6:01 pm, May 15, 2013</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">(For more stories on new cancer data, see )</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">By Julie Steenhuysen</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">CHICAGO, May 15 (Reuters) - Melanoma patients treated with</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">two Bristol-Myers Squibb drugs fared much better than</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">those who received either of the medications individually, a new</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">advance for treatments that harness the body's immune system to</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">fight cancer.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Bristol released preliminary data from the early-stage trial</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">on Wednesday, with more detailed results expected to highlight</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">the American Society of Clinical Oncology's annual meeting in</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Chicago that starts at the end of the month.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Patients in the study received Bristol's immunotherapy</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Yervoy, which is already on the market, and an experimental</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">treatment called Nivolumab that attacks an</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">immune-system-inhibiting protein called PD-1. The combined</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">treatment shrank tumors in a majority of patients.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">"We have never seen this with immunotherapy before," said Dr</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Jedd Wolchok of New York's Memorial Sloan-Kettering Cancer</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Center. "The vast majority of patients have a decrease in tumor</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">burden. In melanoma, we're used to seeing the opposite," he said</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">of the notoriously difficult-to-treat form of skin cancer.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Investors have been eager to see results of the study, with</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Bristol shares reaching a 10-year high on Wednesday in advance</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">of the data release.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Both drugs are designed to target different parts of the</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">immune system that act as brakes even when cancer is present,</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">preventing immune cells from attacking tumors. By gumming up</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">these brakes, the drugs free the immune system to attack and</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">kill tumor cells.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Approved in 2011, Yervoy, or ipilimumab, was the first drug</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">to significantly extend survival in patients with advanced</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">melanoma, the most deadly form of skin cancer. It boosts the</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">immune system by blocking the action of a protein called CTLA-4.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Nivolumab, which is in late-stage testing, targets a protein</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">called PD-1, or Programmed Death receptor, a new class of</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">immune-system drugs that shows promise not only in melanoma but</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">also in lung and kidney cancer.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Typically, only about 11 percent of patients respond to</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Yervoy, and recent studies in melanoma suggest Nivolumab</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">produces a response rate of about 41 percent, Wolchok told a</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">news briefing.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">The current study looked at the combination of the two drugs</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">based on animal studies suggesting that together they might</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">work better than either drug alone.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Wolchok reported results for 86 patients in the trial as of</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">February 2013, including 52 patients who were on both drugs at</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">the same time. In one of the treatment groups, which will likely</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">advance to late-stage trials, 53 percent of patients treated</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">with both Yervoy and Nivolumab simultaneously had an objective</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">response - defined as at least a 50 percent reduction in tumor</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">size.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">RAPID RESPONSE</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Dr Sandra Swain, president of ASCO, called the findings</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">remarkable. "This combination treatment led to a very rapid and</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">profound lasting tumor shrinkage. Ninety percent of patients are</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">still responding," she said.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Three out of four patients who responded to the dual</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">treatment had tumor shrinkage in the first three months.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Among the most advanced melanoma patients, Wolchok said the</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">combination of the two drugs produced "rapid and deep</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">regressions, with many showing more than 80 percent tumor</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">regression by the time of the first scan."</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Overall, most patients had some decrease in tumor size. In</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">31 percent of all patients taking the dual therapy, tumors</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">shrank by greater than 80 percent, Wolchok said.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">In 18 percent of patients, the drug combination produced a</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">complete response, meaning tumors were no longer detectable,</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Wolchok said in an interview. He said they do not yet have any</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">data on relapse because 90 percent of patients who responded to</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">the treatment are continuing to benefit.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">The combination also appeared to be safe. About half of</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">patients who got both treatments had a drug-related side effect,</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">but in most cases it was linked to elevations in enzymes related</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">to the pancreas and liver.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">"These are reversible, sometimes without treatment," Wolchok</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">said, although some patients did need a short course of the</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">steroid prednisone. There were no drug-related deaths.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">"We really didn't see anything new with the combination"</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">related to safety, he said.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Bristol-Myers plans a late-stage clinical trial that looks</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">at both drugs in combination, as well as each separately, in</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">patients with melanoma. It has also begun testing the same</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">combination in lung cancer and renal-cell cancer.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">"We view the combination of immunotherapy as a significant</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">one that we'll be pursuing," Michael Giordano, Bristol-Myers'</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">senior vice president of global development for oncology and </span><br />
<span style="background-color: rgba(255, 255, 255, 0);">immunology, said in an interview.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">So far, Bristol-Myers is furthest ahead in its development</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">of a PD-1 inhibitor, but Merck & Co Inc last month won</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">designation from the U.S. Food and Drug Administration as a</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">"breakthrough therapy," which could speed development and</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">regulatory review of the product.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">In a recent note, Bernstein Research analyst Tim Anderson</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">said Bristol's anti-cancer drug PD-1 "is the major driver of</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">investor interest at the moment," but said awareness is building</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">that competitors "may not be very far behind."</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Last November, Merck reported results from a trial of its</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">drug in patients with advanced melanoma and saw a 47 percent</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">response rate. In that trial, the drug benefited patients who</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">had previously been treated with ipilimumab but had not</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">responded, said Dr. Gary Gilliland, a Merck senior vice</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">president for oncology.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Merck plans to present an update of this study on June 2 at</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">the ASCO meeting. Gilliland said the company also is studying</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">its treatment in so-called triple-negative breast cancer, a</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">hard-to-treat form of the disease, as well as head and neck</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">cancer and bladder cancer.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">Other companies pursuing the PD-1 or related pathways</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">include Roche, GlaxoSmithKline and Teva</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">"PD-1 is arguably the most exciting breakthrough in cancer</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">therapy in a decade," said ISI Group analyst Mark Schoenebaum.</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">"There is speculation that it might offer a cure for some</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">patients with solid tumors. This is unprecedented."</span><br />
<span style="background-color: rgba(255, 255, 255, 0);"><br /></span>
<span style="background-color: rgba(255, 255, 255, 0);">(Additional reporting by Bill Berkrot in New York; Editing by</span><br />
<span style="background-color: rgba(255, 255, 255, 0);">Michele Gershberg and Prudence Crowther)</span><br />
<div>
<br /></div>
<br />
<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~<br />
Charles Darwin~<br />
Take Care,<br />
Jimmy B<br />
<br />
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<img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" />jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com3tag:blogger.com,1999:blog-836586378132117060.post-81166876702635032532013-01-10T16:22:00.000-05:002013-01-10T16:22:36.754-05:00Pearls of Wisdom: Melanoma ..Jim BreitfellerPearls of Wisdom: Melanoma <br />
Reviewed by Douglas Johnson, MD and Jeffrey Sosman, MD<br /><br />
This entry was posted on Tuesday, January 8, 2013 at 6:33 pm <strong><u><span style="color: red;">Management of Advanced Disease</span></u></strong><br />
<strong><u><span style="color: red;"></span></u></strong><br /><br />
Metastatic melanoma historically has had a very poor prognosis with a median survival of 6-9 months. However, recent advances in molecularly targeted therapy as well as immune based therapies have provided several effective treatment options for oncologists and their patients. In 2012 there are several important issues to consider in the management of patients with newly diagnosed advanced melanoma.<br />
<br /><br />
<strong>Advanced Stage III/Stage IV resectable disease</strong><br />
<br />
• In patients with advanced stage III disease or oligometastatic disease, consultation with an experienced surgical oncologist is warranted, as patients can experience long term survival with an aggressive surgical approach. Despite the advances in systemic therapy, surgical resection is still our preferred option in most of these clinical situations. One series of 64 patients showed a >30% four year survival in patients who had completely resected metastatic disease.1<br />
<br />
•Another option we have offered is a short course of systemic therapy for 6-12 months prior to surgery with the intent to improve the chance that rapid recurrence of disease does not occur and to define the tumor’s responsiveness to the treatment.<br />
•Patients should be considered for clinical trials in the adjuvant setting. Studies are ongoing to assess whether ipilimumab or vemurafenib is effective in preventing recurrences in high risk patients. For stage IV (M1) disease after complete surgical treatment there is no standard of care adjuvant treatment.<br />
<br /><br />
•Interferon, the current standard of care for fully resected stage IIb-III disease, is also an option in the adjuvant setting.<br />
<strong>Molecular Testing</strong><br />
<br />
•All patients with metastatic disease should undergo testing for BRAF V600 mutations given the availability of targeted therapy for this mutation. This should include testing for the alternate V600 mutations that make up about 20% of BRAF mutations at this codon and appear sensitive to the BRAF inhibitors such as vemurafenib and dabrafenib.2 Patients with advanced local or regional disease can also be considered for testing since there are a number of clinical trials either recently or soon to be activated with BRAF inhibitor based therapy in BRAF V600 mutated melanoma at stage IIC-IIIC. Additionally, results will be available on progression so that therapy can be rapidly initiated if needed.<br />
•Evaluation of several KIT mutations should also be considered in at least specific clinically defined subsets of patients. Though KIT mutations are present in only ~2% of all melanomas, acral (feet and hands) and mucosal melanomas harbor KIT mutations in 15-20% of cases. KIT mutations are sensitive to imatinib in about 25% of the cases based on limited numbers of patients.3<br />
•NRAS mutations are also present in 15-20% of patients and though no targeted therapies are yet established as standard for this subset, there are a number of studies underway specifically targeting this mutation. Furthermore, the NRAS mutation may confer a poor prognosis to the melanoma.4<br />
<br /><br />
Standard therapies for metastatic disease<br /><br />
<strong>Vemurafenib</strong><br />
Vemurafenib is a BRAF inhibitor approved for patients with metastatic melanoma with BRAF V600 mutations (40-50%). In phase III trial data, objective tumor shrinkage was seen in well over 50% of patients, and clinical benefit seen in nearly all patients during the initial few weeks of administration. Median progression-free survival was 6.9 months (compared to 1.6 months with dacarbazine).5 Some important points regarding vemurafenib therapy:<br />
•Responses are often rapid and dramatic. If patients with mutated BRAF V600 melanoma are highly symptomatic, vemurafenib would be our first line therapy in nearly all such patients.<br />
•Patients will inevitably progress or relapse, often within the first year. Strategies to prevent or delay resistance are being pursued. In fact, recently the addition of a MEK inhibitor, trametinib, demonstrated an ability to improve the frequency of objective responses and the duration of progression-free survival in those melanoma patients receiving dabrafenib (BRAF inhibitor).<br />
•Vemurafenib has clinical activity in patients with brain metastases in small series. Prospective phase II trials are pending completion. Trials with dabrafenib have also demonstrated frequent clinical benefits in such patients.6<br />
•Secondary squamous cell carcinomas are common in BRAF inhibitor trials (10-25%).7 Suspicious lesions should be biopsied. Additionally, secondary melanomas and CMML have been reported in the presence of vemurafenib; almost certainly the drug has played a role to accelerate the appearance and growth of these tumors.<br />
<strong>Ipilimumab (Yervoy)</strong><br />
<strong></strong><br /><br />
Ipilimumab is an antibody to CTLA-4 and functions as an immune checkpoint inhibitor. This “removes the brakes” on the immune system which decreases immune tolerance to the tumor but may also cause autoimmune toxicities. In phase III trials, overall survival was increased compared to a vaccine in previously treated patients (10 mos vs. 6.4 mos), and in combination with dacarbazine compared with dacarbazine alone in the first line setting (11.2 vs. 9.1 months).8,9 Some important points to consider:<br />
•Tumor burden on exam or on imaging may transiently worsen even in patients destined to respond. We do not repeat imaging until after 12 weeks of therapy unless the patient develops concerning new or progressive symptoms.<br />
•Since even responding patients may have tumor growth or slow shrinkage, we are hesitant to use this therapy in highly symptomatic patients, especially if there are reasonable alternatives.<br />
•Autoimmune side effects may be severe. Colitis, hepatitis, dermatitis, neuropathy, and endocrinopathies are the most common toxicities.<br />
•Patients should be monitored closely for colitis. Concerning symptoms (diarrhea, melena/hematochezia, abdominal pain) require rapid evaluation. Though Imodium is appropriate for mild diarrhea (grade I), grade II toxicities or worse require prompt initiation of steroids. Colonoscopy should be performed to confirm the diagnosis in patients with severe colitis. Bowel perforation and death have been reported in extreme cases almost always when initial therapy is delayed.<br />
•Headaches, with or without vision changes and fatigue may represent hypophysitis. Evaluation of TSH, cortisol, and testosterone, and brain MRI can aid in this diagnosis.<br />
•We monitor TSH, cortisol, and liver enzymes at every visit.<br />
<br />
•Other rare immune mediated side effects such as Guillan Barre syndrome, myasthenia gravis, sarcoidosis, and hemophilia have also been described.<br />
<strong>Interleukin-2 (IL-2)</strong><br />
<strong></strong><br /><br />
IL-2 has been used for many years in treating metastatic melanoma. It is associated with <strong>6% durable remission rate (cures) and 15-20% overall response rate</strong>.10 Its use is limited to centers familiar with the associated severe side effects. Some points to consider when treating or referring patients:<br />
<br /><br />
•Therapy is limited to healthy patients usually under 70 years of age with adequate cardiac, pulmonary, renal, hepatic, and hematopoietic organ function and well controlled brain metastases. Nearly all patients experience treatment associated hypotension, multi-organ dysfunction, and vascular leak syndrome<br /><br />
•Though newer agents exist, IL-2 has the most long term data showing durable remissions in the minority of patients. We still consider this therapy in interested, eligible patients.<br />
•Advantages of using IL-2 compared to ipilimumab include longer duration of use and more rapid assessments of benefit (8 weeks vs. 12+ weeks). Advantages to ipilimumab include outpatient use, generally less severe side effects, and possibly higher rates of durable remissions.<br />
<br />
<br />
<br />
<strong>Cytotoxic chemotherapy</strong><br />
<br />
•Dacarbazine, temazolamide, and carboplatin/paclitaxel occasionally benefit patients with metastatic disease.<br />
•No consistent survival benefit has been demonstrated with cytotoxic chemotherapy. Response rates are typically in the 5-10% range.<br />
•We use chemotherapy only in patients who are not eligible for other therapies.<br />
Which therapy should be chosen as first line therapy in patients with BRAF V600E/K mutations?<br />
•This decision should be individualized. No head to head comparisons have been done with immunotherapy in the form of ipilimumab or interleukin-2 therapy. BRAF inhibitors are associated with high response rates but inevitable progression, while immune therapies have low objective response rates but durable remissions in a minority of patients.<br />
<br />
•In patients with rapidly progressive or highly symptomatic disease, we typically use vemurafenib. In patients with asymptomatic disease, we favor immune based therapies for interested patients. An intergroup randomized cross over trial will address this issue, where half the patients start with vemurafenib and the other half on ipilimumab.<br />
<br />
<br />
<br />
<strong>Promising Therapies</strong><br />
<br /><br />
Therapy for metastatic melanoma is rapidly evolving. Many clinical trials are ongoing, and patients should be encouraged to participate in clinical trials for first line therapy or at progression if treated with standard therapy options. Some therapies that are likely to be approved are listed below.<br />
•BRAF/MEK inhibitor combination therapies: Dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) have both shown benefit individually over dacarbazine in phase III trials in patients with BRAF mutant metastatic melanoma. However, interest lies especially in combination therapy to delay resistance and disease progression. In a randomized phase II trial, combination therapy was associated with an improved objective response rate (54% vs 76%) and progression free survival compared to dabrafenib alone (9.4mo vs. 5.8mo).11 Additionally, the incidence of squamous cell carcinomas was dramatically decreased with combination therapy. Trials are ongoing comparing this combination with vemurafenib in untreated patients with BRAF mutations. An additional trial is evaluating vemurafenib in combination with GDC-0973, a MEK inhibitor.<br />
<br />
<br />
<br />
<strong>•Anti-PD-1 therapy:</strong> <br />
<br />
Several newer checkpoint inhibitors block the interaction between PD-1 (expressed on T-cells) and PD-L1 (expressed on tumor) which activates the immune system, hopefully in a tumor specific manner. A phase I trial with nivolumab (anti-PD1 BMS) data shows a 31% response rate with fewer autoimmune side effects than ipilimumab.12 Pneumonitis was described in several patients. Trials are ongoing in patients who have progressed on ipilimumab. Early reports of another anti-PD1, MK-3475 also show a remarkable response rate in patients either following Ipilimumab or de novo in the 40-50% response range.<br />
<br />
<strong>•Anti-PD-1 + Yervoy therapy:</strong><br />
<br />
By using both Checkpoint inhibitors, you and block two pathways that the melanoma can't use for immunosuppression. This allows the activated T-cells to go unchecked and keeps the immune response switch on. This clinical trial is ongoing at Sloan Kettering, and Yale. Rumor has it that they are seeing high response rates.<br />
<br />
<br />
<br />
References<br />
<br />
1.<br />
<br />
Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group Clinical Trial S9430. Cancer 2011.<br />
2.<br />
<br />
Lovly CM, Dahlman KB, Fohn LE, et al. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PloS one 2012;7:e35309.<br />
3.<br />
<br />
Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA : the journal of the American Medical Association 2011;305:2327-34.<br />
4.<br />
<br />
Devitt B, Liu W, Salemi R, et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment cell & melanoma research 2011;24:666-72.<br />
<br /><br />
5.<br />
<br />
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England journal of medicine 2011;364:2507-16.
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
~Charles Darwin~<br />
Take Care, <br />
Jimmy B <br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-5685841296588515412013-01-07T13:42:00.002-05:002013-01-07T13:50:53.215-05:00ASCO 2013.. The comming out party for Combination Therapy!!! Yervoy + Anti-PD-1 ..Melanoma. Jim Breitfeller<div class="MsoNormal" style="margin: 0in 0in 0pt; mso-layout-grid-align: none;">
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjCZXiHM6s3MdpGzWJt5VHmvLqMOwgMORQeKlaCQnM7rETSVRGgSGF_uWCpZJWwXs4-HHsNGvYb-lkep4kB4OPpFOsiQDgJyAEBz5HAaSbKfVriJbe3MikvQ0zPiCdyVaf2i2-qXtfjeCM/s1600/Unlock+the+immune+response+with+Yervoy+and+Anti-PD-1.jpg" imageanchor="1" style="clear: left; cssfloat: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" eea="true" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjCZXiHM6s3MdpGzWJt5VHmvLqMOwgMORQeKlaCQnM7rETSVRGgSGF_uWCpZJWwXs4-HHsNGvYb-lkep4kB4OPpFOsiQDgJyAEBz5HAaSbKfVriJbe3MikvQ0zPiCdyVaf2i2-qXtfjeCM/s320/Unlock+the+immune+response+with+Yervoy+and+Anti-PD-1.jpg" width="320" /></a><span style="color: windowtext; font-weight: normal; mso-bidi-font-family: ArialMT; mso-font-kerning: 0pt;">ASCO 2012 was PD-1’s debutant ball, but we may have found a partner (Yervoy) at this Year’s 2013 Ball and may be only a few years away from its coronation (FDA’s approval) as a stand alone or combinatorial therapy. I believe that ASCO 2013 will be the coming out party for combination therapy of Anti-PD-1 + Yervoy.<o:p></o:p></span></div>
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<span style="color: windowtext; font-weight: normal; mso-bidi-font-family: ArialMT; mso-font-kerning: 0pt;">Using this combination blocks two checkpoint pathways on the T-Cells leaving it activated to proliferate and destroy the cancer.<o:p></o:p></span></div>
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<a href="http://i384.photobucket.com/albums/oo290/jimmy_b/Tregs-3.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" eea="true" height="171" src="http://i384.photobucket.com/albums/oo290/jimmy_b/Tregs-3.jpg" width="400" /></a></div>
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<span style="font-family: 'Times New Roman'; font-size: 12pt; mso-ansi-language: EN-US; mso-bidi-font-family: ArialMT; mso-bidi-language: AR-SA; mso-fareast-font-family: 'Times New Roman'; mso-fareast-language: EN-US;">If you add Yervoy & Anti-PD-1 to the therapy you have a better chance to activate the CD4 and CD8 T-cells</span><br />
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<a href="http://i384.photobucket.com/albums/oo290/jimmy_b/T-cell-4.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" eea="true" height="222" src="http://i384.photobucket.com/albums/oo290/jimmy_b/T-cell-4.jpg" width="400" /></a></div>
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<a href="http://i384.photobucket.com/albums/oo290/jimmy_b/SynergisticActivity-5.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" eea="true" height="338" src="http://i384.photobucket.com/albums/oo290/jimmy_b/SynergisticActivity-5.jpg" width="400" /></a></div>
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<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
~Charles Darwin~ <br />
Take Care, <br />
<br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-2810527589089292732012-10-26T11:21:00.000-04:002012-10-26T12:05:34.662-04:00How to integrate immunotherapies into treatment timelines? Timing is everything! Melanoma..Jim BreitfellerDr. Gomella,<br />
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I want to thank you for sharing your thoughts on immunotherapy in the article in “High Points and Hurdles: Immunotherapy Moves Forward” online at OncLive.<br />
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As a patient/survivor/researcher of stage IV melanoma I know first hand of the importance of integrating immunotherapy into a patient’s treatment. Timing of the therapy is everything, along with the patient’s tumor burden and stage. <br />
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In the early phase of cancer, the tumor cells are trying to establish a foothold in a foreign land. They do this by recruiting Tregs with cytokines (Il-10, TFG-b etc.) along with chemoattractants and suppressive cells. <br />
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Two of the first arrivals are Tregs along with IL-10. In the early phase of cancer, it has been discovered that the patient’s Tregs are elevated along with IL-10 concentration.<br />
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So when the macrophages and immune cells arrive at the tumor’s microenvironment, they encounter suppressive conditions allowing the tumor to continue with growth and progress. The elevated IL-10, IL-4 concentration polarizes the monocyte to the M2, and the T-cells to the Th2 phenotypes and shutting down the immune response.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgaVh8irAI-288sckw6LksywYl0ErWcM7JQf4GzIMhCjl7sUbdyF0fUeIzT5wbiZdUXzsD-klBjv_VX8PBEAAAuC1kBbXZoSpC-0NXmEk_zo_P48K6OYPgKVtvCzUIaxhDY1jDlpOjUQWg/s1600/Polarization+of+Macrophage+function-1.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img alt="" border="0" height="326" oea="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgaVh8irAI-288sckw6LksywYl0ErWcM7JQf4GzIMhCjl7sUbdyF0fUeIzT5wbiZdUXzsD-klBjv_VX8PBEAAAuC1kBbXZoSpC-0NXmEk_zo_P48K6OYPgKVtvCzUIaxhDY1jDlpOjUQWg/s400/Polarization+of+Macrophage+function-1.jpg" title="" width="400" /></a></div>
<strong>The macrophage also secretes some chemokines (CCL17, CCL22& CCL18). These chemokines attract other cells that have the cell surface chemokine receptors such as CCR4.</strong><br />
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Treg cell migration to Melanoma tumors is mediated by CCL22 released by cancer cells and tumor-associated macrophages. This cytokine plays a role in the trafficking of activated/effector T-lymphocytes to inflammatory sites and other aspects of activated T-lymphocyte physiology. Chemotactic for monocytes, dendritic cells and natural killer cells. Mild chemoattractant for primary activated T-lymphocytes and a potent chemoattractant for chronically activated T-lymphocytes but has no chemoattractant activity for neutrophils, eosinophils, and resting T-lymphocytes This attraction is the beginning of the suprresiveness of the the tumor’s microenviroment.<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4z6Fw2Vpff31sYrlnlbJYM5I_hKvgUZ6OhQRwbruIWMEVFvDoReZJ_v2-ttj5m3uCk_AkQ3XAWQ8soYQtc1602UDkBZy2cXc7svqf-yxlYsI7rHk2BElG8Rr6TIzKcWpYqzzWE-PDOrQ/s1600/Polarization+of+Tumor+Assoicated+Macrophage+function-2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="301" oea="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg4z6Fw2Vpff31sYrlnlbJYM5I_hKvgUZ6OhQRwbruIWMEVFvDoReZJ_v2-ttj5m3uCk_AkQ3XAWQ8soYQtc1602UDkBZy2cXc7svqf-yxlYsI7rHk2BElG8Rr6TIzKcWpYqzzWE-PDOrQ/s400/Polarization+of+Tumor+Assoicated+Macrophage+function-2.jpg" width="400" /></a></div>
<strong>TAM exert strong immune suppressive activity, not only by producing IL-10 but also by the secretion of chemokines (e.g., CCL17 and CCL22), which preferentially attract T cell subsets devoid of cytotoxic functions such as Treg and Th2.</strong><br />
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<strong>IL-10 promotes the development of a type 2 cytokine pattern by inhibiting the IFN-γ production of T lymphocytes particularly via the suppression of IL-12 synthesis in accessory cells. </strong><br />
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<strong><span style="color: red;">IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines</span></strong></div>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggJcX_1QbWmDL0en3WgwSaUmFifFiY-lgJBKDo5g3xAqQr9x-gg6Vjo1-uUuHc8FKnCwa8SB4twxd6HBS7CsXH27_DhRKfs9IN-tehxBcoUxlxaVqbXrL2LhB_LoxkhGqQnzAdsP_pCLM/s1600/Tumors+Microenvirnment-4.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="265" oea="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggJcX_1QbWmDL0en3WgwSaUmFifFiY-lgJBKDo5g3xAqQr9x-gg6Vjo1-uUuHc8FKnCwa8SB4twxd6HBS7CsXH27_DhRKfs9IN-tehxBcoUxlxaVqbXrL2LhB_LoxkhGqQnzAdsP_pCLM/s400/Tumors+Microenvirnment-4.jpg" width="400" /></a></div>
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<u><strong>So how can we integrate immunotherapies into treatment timelines to generate the wanted immune response toward the cancer?</strong></u><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhAwzQ6ReahPhsyAhU58Yp3stbOLrNDKcsh8JXbzl6KyQhegEKR4nY_922XQNAUqU187Z_iFdTSrpCbjGDmPjAzh65sEtGclNOl67nWDWIs8qEGXPAwL48q3vdNE1unS4ASPlyyyBv3aKs/s1600/Tumor+Burden-5.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="271" oea="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhAwzQ6ReahPhsyAhU58Yp3stbOLrNDKcsh8JXbzl6KyQhegEKR4nY_922XQNAUqU187Z_iFdTSrpCbjGDmPjAzh65sEtGclNOl67nWDWIs8qEGXPAwL48q3vdNE1unS4ASPlyyyBv3aKs/s400/Tumor+Burden-5.jpg" width="400" /></a></div>
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<ol>
<li>First, you need to evaluate the cancer patient and establish their stage. </li>
<li>Second, check the tumor’s genetic code for mutations.</li>
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<li>Third, evaluate the patient’s overall health and the ability to go through the therapy<br /><br />Here is a generic graphic on how to activate an innate and adaptive response.</li>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiqxrGXufQ0QwHNlXOmgMi3WtfYX6wUXMWnhLV-_JJb7tJ_R8WStkrUNP9I8EoEkiHyTn6wGo9XWfu5EgKFnvqprGyXCmgDZowL2T8ikyrTKIiogWO7z6YiQWeVoFeRjhUrb-008acfnuw/s1600/Immune+Response-6.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="400" oea="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiqxrGXufQ0QwHNlXOmgMi3WtfYX6wUXMWnhLV-_JJb7tJ_R8WStkrUNP9I8EoEkiHyTn6wGo9XWfu5EgKFnvqprGyXCmgDZowL2T8ikyrTKIiogWO7z6YiQWeVoFeRjhUrb-008acfnuw/s400/Immune+Response-6.jpg" width="383" /></a><br />
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1) You need to generate tumor-associated Antigens <br />
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2) You need to generate “The Danger Signal” (proinflammatory cytokines secreted, IL-1, IL-6, IL-12, TNF-alpha, Nitric Oxide, PGE2) <br />
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3) Block the Suppressive factors that inhibit T-cell activation (Anti-CTLA-4, Anti-PD-1, Anti IL-10r) IL-10 suppresses many functions of (NK) cells and T cells, primarily by preventing APCs from producing proinflammatory cytokines, “The Danger Signal”)<br />
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4) Tilt the T-cell Differentiation toward the TH1 phenotype and the Macrophage (TAM), Tumor Associated Macrophage polarization toward the M1 phenotype<br />
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5) Alter the tumor’s Microenvironment (addition of Multikine)<br />
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6) Produce activated CTLs and Memory T-cells(addition of IL-2)<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjfpm99U8OWZs1vyCeybI5otQmnLGE8nuDUZ2O7LdTfhb46hikrRwsunvyRoGcVI1X9_wUv3-OyTYTlPT0hxkz1Ob14yd58RMJ0i2amGyD4su2tTgVcJ67i5OyJfokXoFztdkehXHTdozg/s1600/Combinatorial+Therapy-7.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="232" oea="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjfpm99U8OWZs1vyCeybI5otQmnLGE8nuDUZ2O7LdTfhb46hikrRwsunvyRoGcVI1X9_wUv3-OyTYTlPT0hxkz1Ob14yd58RMJ0i2amGyD4su2tTgVcJ67i5OyJfokXoFztdkehXHTdozg/s400/Combinatorial+Therapy-7.jpg" width="400" /></a></div>
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The Bottom line is we need Sequential Combinatorial Therapy with timing and dosage as the major limiting factors in creating the innate and adaptive immune response. <br />
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“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”<br />
<br />
~Charles Darwin~ <br />
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Take Care, <br />
<br />
Jimmy B <br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com2tag:blogger.com,1999:blog-836586378132117060.post-27581930519011508022012-09-21T18:18:00.000-04:002012-09-21T18:18:44.211-04:00Legislation for Combinatorial Therapy >> Melanoma ..Jim BreitfellerCongressman Bilbray, and Congresswomen Maloney and DeLaura are submitting legislation today that, if passed, will provide extended patent protection for investigational drugs that are tested in combination. This will provide a major financial incentive for industry to do the kinds of studies they now find difficult but which offer the best hope for melanoma patients.
This legislation came out of meetings MRF had with Congressman Bilbray, whose daughter has Stage III melanoma. We proposed the idea to the Congressman and provided a background document showing how similar action in pediatrics and some infectious diseases has resulted in tremendous progress in drug development.
Most doctors agree that real advances in effective treatments will only come through combining two or more drugs together. If these drugs are already approved, doing studies like this are relatively easy. If they are not yet approved--still in clinical trials--they are very difficult. Companies worry that any side effects that arise from a combination study will "taint" the data of their drug and hurt its chances of approval. And they are reluctant to collaborate with other companies on these studies. This legislation will add a "carrot" to the mix and will help accelerate these important studies.
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj4nk_26aBMrYbJiLFcBmbotfscTzqVAMQMxEEnzxHNB7gquMKzxLt4ApRLU2iLFH-BLVXFQl-S6gY41pGeiMP4_RzoWAYCpI_KFas2RscNdnfV-sGYiZ59PwTMnX8C3Oq9zy03sZW3dFM/s1600/The+Ultimate+Treatment.jpg" imageanchor="1" style="clear:left; float:left;margin-right:1em; margin-bottom:1em"><img border="0" height="237" width="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj4nk_26aBMrYbJiLFcBmbotfscTzqVAMQMxEEnzxHNB7gquMKzxLt4ApRLU2iLFH-BLVXFQl-S6gY41pGeiMP4_RzoWAYCpI_KFas2RscNdnfV-sGYiZ59PwTMnX8C3Oq9zy03sZW3dFM/s400/The+Ultimate+Treatment.jpg" /></a></div>
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view¤t=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" border="0" alt="Photobucket"></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-15997993431946296752012-09-21T12:15:00.000-04:002012-10-11T09:35:30.333-04:00You and Your Doctor—Tackling Your Cancer Together..Melanoma..Jim BreitfellerYou and Your Doctor—Tackling Your Cancer Together<br />
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Talking with your doctor openly about your diagnosis and treatment—and keeping informed every step of the way—will help you work with your doctor to make the best possible decisions about your treatment.<br />
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<span style="color: red;"> <b>Educate yourself</b></span><br />
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Visit websites designed to educate and assist patients with your type of cancer.<br />
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Ask your doctor where you can learn more about your cancer, its treatment and any ongoing research. <br />
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Be informed when you talk to your doctor and treatment team. <br />
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Ask questions and be proactive. <br />
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It’s your health—and your life! <br />
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Talk openly with your doctor Molecular testing for cancer-related genes may not be right for everyone, but by staying informed and asking about such testing, you can be sure that every avenue for treating your cancer has been explored. And for you, that may make the difference between treatment that is effective, or not. <br />
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<span style="color: red;"><strong>Here are some questions you might ask your doctor: </strong></span><br />
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Are there gene mutations identified for my type of cancer?<br />
Should my tumor be tested for gene mutations? <br />
What can molecular testing tell me about my cancer? <br />
What can molecular testing tell me about my prognosis? <br />
How might molecular testing affect my treatment plan? <br />
How can I get my tumor or biopsy tested?<br />
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<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
<br />
~Charles Darwin~ <br />
<br />
Take Care, <br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-53266037838460702982012-07-12T11:20:00.000-04:002012-07-12T11:53:18.577-04:00Toronto man dies without access to Bristol-Myers Squibb experimental drug..Melanoma.Jim BreitfellerPublished on Wednesday July 11, 2012 <br />
<br />
<br />
Doherty, 48, died in his Toronto home Tuesday after months of publicly fighting for access to a trial-stage melanoma drug. <br />
<br />
<br />
Despite pleas from his family, his doctor’s approval and a change.org petition just shy of 200,000 signatures, Bristol-Myers Squibb (BMS) repeatedly refused to provide Doherty with compassionate access to its drug, saying it was not yet safe for use outside clinical trials.<br />
<br />
His death raises the question: For a patient with no other chance at survival, do drug companies have the responsibility to let them try a drug even if it could harm them? <br />
This particular drug, immune system off-switch blocker BMS-936558, showed early signs of success in phase one testing but is not yet safe for use outside clinical trials, BMS told the Star. <br />
“While we are unable to comment on specific patient cases, we have the deepest sympathy for those who have lost loved ones to cancer,” company spokeswoman Sonia Choi said in an email Wednesday.<br />
<br />
The best way to make cancer medicine broadly available to patients, Choi wrote, is through “carefully controlled clinical trials” that establish the risks and benefits, and “by working with health authorities to successfully register these medicines.” <br />
But when Doherty had cancer in 2007, he responded well to a similar, then-experimental BMS drug. His family felt his medical history made him a good candidate for the new drug — besides, when the cancer returned, they had nothing to lose. <br />
<br />
“Obviously we are tremendously upset and disappointed that they chose not to make the exception,” said Doug Boyce, Doherty’s lifelong friend, on the phone from Vancouver. <br />
<br />
More than that, Boyce said, friends and family are sad and disappointed that there seems to be no system in place for people who reach the end of treatment options to safely access new drugs from pharmaceuticals, without the company fearing ramifications if the drug fails. “It would seem there’s a gap there.” <br />
<br />
Doherty was a caring, giving man who was most proud of his family, Boyce said, his voice breaking. The men grew up together in Oshawa, spending many hours at various cottages, pools and golf courses over the years. Boyce remembers his friend as the man who, when given a month to live in 2007, tossed the papers aside and said, “We won’t speak of that again.”<br />
<br />
Doherty’s wife, Rebecca Cumming, thanked the public for the support over the past month and directed donations to the David Cornfield Melanoma Fund or the Princess Margaret Hospital Foundation. <br />
<br />
“We always remained hopeful that BMS would change its mind and Darcy would have another miracle. Sadly, that did not happen.<br />
<br />
Source:http://www.thestar.com/news/gta/article/1225109--toronto-man-dies-without-access-to-bristol-myers-squibb-experimental-drug<br />
<br />
<strong><u>Commentary by a Stage IV Melanoma Survivor:</u></strong><br />
<br />
Bristol-Myers Squibb should be ashamed of itself and should be held accountable for the premature death of Mr. Daoherty. BMY could have granted an exception to their rules and allowed Darcy compassionate care due to the fact that he had no other option.<br />
<br />
This puts BMS in a very unethical stance with EGG on their face. (Mr. Lamberto Andreotti)<br />
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Bristol-Myers Squibb needs cancer patients to enroll in their clinical trials to test them for <strong>efficacy. Without the patient, there would be no trial, no FDA approval, and no product.</strong> The patient plays a critical role in the <span class="st"><strong>Commercialization</strong> of this new drug</span>. <span style="color: red;"><strong>So why did BMS refuse compassionate use?</strong> </span><span style="color: black;">It wasn't because they would loose money? They have reeped benefit of Yervoy and their other drug revenues to pay cash to </span>acquire <strong>Amylin</strong> Pharmaceuticals Inc. <strong>The price (5.3 billion dollars) in CASH!!!!! Bristol could have given away 4 doses to this dying man as the last hope, but no, Bristol Myers refused!!!!</strong><br />
<br />
<strong>Is Bristol-Myers committed to their social responsiblity, " Help save lives???</strong><br />
<br />
<strong>Was their Behavoir Ethical??? Or is it all about GREED???</strong><br />
<br />
<strong>I think it is the latter. This is not the first time that this situation has reared it's ugly head. There were many Patients that lost their lives because Bristol-Myers Squibb closed it's compassionate use of Yervoy for melanoma patientsts, only to open new Clinical trials to create a shortage for the drug. </strong><br />
<br />
<strong>As a share holder of this company, I am a shamed of their ethical practices.</strong><br />
<br />
<strong>Here is what is posted on their website.</strong><br />
<br />
<strong>Our Commitment</strong>“
<br />
To our patients and customers, employees, global communities, shareholders, environment and other stakeholders, we promise to act on our belief that the priceless ingredient of every product is the integrity of its maker. We operate with effective governance and high standards of ethical behavior. We seek transparency and dialogue with our stakeholders to improve our understanding of their needs. We take our commitment to economic, social and environmental sustainability seriously, and extend this expectation to our partners and suppliers.<br />
<br />
In our mission to discover, develop and deliver innovative medicines that help patients prevail over serious diseases, we support a clean and healthy environment and subscribe to policies and practices that merit the trust and confidence of our society.<br />
<br />
<br />
<span style="color: red;">This is all LIP SERVICE!!!!!!!</span><br />
<br />
<br />
<br />It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”<br />
<br />
~Charles Darwin~<br />
<br />
<br />
Take Care, <br />
<br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a><br />
<br />jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-81193025093586185762012-07-04T18:04:00.000-04:002012-07-04T18:04:49.040-04:00Interview With Michael B. Atkins, MD Immunotherapies in Melanoma.Jim Breitfeller<strong><span style="color: #990000;">Interview With Michael B. Atkins, MD Immunotherapies in Melanoma</span></strong>: Taking Stock<br />
Alice Goodman, MA; Michael B. Atkins, MD<br />
<br />
Posted: 07/02/2012<br />
<br />
Editor's Note: Immunotherapy is the only treatment that can produce durable tumor regression in patients with metastatic melanoma. With novel molecularly targeted agents also being developed for metastatic melanoma, the hope is to learn how to combine and sequence these therapies and improve survival for patients with this once universally fatal disease. At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®), Dr. Michael B. Atkins, Deputy Director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, chaired an educational session on immunotherapy in advanced melanoma.<br />
<br />
Medscape caught up with Dr. Atkins to ask him to put into perspective the emerging data on immunotherapy and what questions still need to be answered. <br />
<br />
IL-2 Opens the Door Medscape:<br />
<strong>What was the first immunotherapy to show an effect in metastatic melanoma?</strong> <br />
<br />
<strong>Dr. Atkins:</strong> High-dose interleukin (IL)-2 received US Food and Drug Administration (FDA) approval for the treatment of patients with metastatic melanoma in 1998. A number of durable responses were observed and 11% of patients were alive at 5 years.[1] More recent studies have shown that patients with elevated lactate dehydrogenase (LDH) levels are much less likely to respond to IL-2, with about a 6% response rate in patients with elevated LDH (all partial responses) and about 21% in those with normal LDH levels.[2] Analysis of molecular profiles shows that a significantly larger proportion of patients with BRAF- and NRAS-mutated tumors respond to IL-2 than those who do not have these mutations. Also, we now have information suggesting that tumors with an inflamed phenotype and immune infiltrates have a 2- to 3-fold improved chance of response relative to those with a noninflamed gene expression pattern. <br />
<br />
<strong>Michael B. Atkins, MD </strong><br />
<strong>Medscape:</strong> Has IL-2 been combined with other immunotherapies? <br />
<br />
<strong>Dr. Atkins:</strong><br />
IL-2 has been combined with vaccine therapy. Results of a randomized trial found that the combination of IL-2 plus vaccine produced response rates of 22.1% compared with 9.7% with IL-2 alone, and a trend was observed toward improved overall survival.[3] Median survival was 17.6 months with the combination of IL-2 plus vaccine vs 12.8 months with IL-2 alone. Very few relapses were seen beyond 2 years in responding patients, a hallmark of effective immunotherapy. However, lower-than-expected response rates were reported for the IL-2-alone group, calling into question how much of an advance this treatment is. Some questions remain: Is this a proof of concept that the immune response can be focused by a vaccine? Will the findings be relevant with novel immunotherapies? Ipilimumab: A Check-Plus for a Checkpoint Inhibitor Medscape: More recently, ipilimumab, a different type of immunotherapy, was approved by the FDA for the treatment of metastatic melanoma. This drug is referred to as the first checkpoint inhibitor, meaning that it interferes with an important downregulatory property of the immune response. <br />
<br />
How does this drug work, and what kinds of outcomes does it achieve? <br />
<br />
<strong>Dr Atkins:</strong> The monoclonal antibody ipilimumab blocks CTLA-4, which serves as a coregulatory protein that shuts off the immune response when it binds to a protein on antigen-presenting cells. Blocking CTLA-4 restores immunity. Ipilimumab has been evaluated in a variety of clinical trials. It is administered intravenously once every 3 weeks for 4 doses on an outpatient basis. Its side effects result primarily from induction of immune reactions against normal tissues, but in general, it produces fewer inflammatory systems (eg, fever, chills, hypotension) than those associated with high-dose IL-2. A recent trial compared ipilimumab plus gp100 vaccine vs ipilimumab alone vs the vaccine alone.[4] In both ipilimumab-containing arms, survival was prolonged. One-year survival was 46%, 44%, and 26% for the 3 arms, respectively. Two-year survival was 22%, 24%, and 14%. Few deaths occurred in the ipilimumab-treated patients after 30 months. <br />
<br />
<strong>Medscape:</strong> What about the safety profile of ipilimumab and patient selection? <br />
<br />
<strong>Dr Atkins:</strong> <br />
The toxicities of ipilimumab are related to activation of the immune system and include colitis, dermatitis, endocrine effects, and hepatitis. In clinical trials, all subgroups benefitted from ipilimumab, with the possible exception of patients with elevated LDH. One feature of ipilimumab is apparent disease progression early in the course of treatment followed by a major response, so we have learned that the effect of treatment is not seen immediately. Pooled data from clinical trials suggest that about 25% of patients with metastatic melanoma have long-term benefit from ipilimumab therapy, and the benefit might be greater with a higher dose of the drug. Also, there is a potential role for maintenance therapy with this agent. <br />
<br />
<strong>Medscape:</strong> Has ipilimumab been studied in combination therapy? <br />
<br />
<strong>Dr Atkins</strong>: <br />
A study was conducted in previously untreated patients with metastatic melanoma in which the patients were randomly assigned to dacarbazine alone or dacarbazine plus ipilimumab.[5] Some experts expected better results than were achieved in this first-line setting, and it is possible that dacarbazine may have compromised outcomes. <br />
<br />
<strong>Medscape</strong>: What are the take-home messages about ipilimumab for metastatic melanoma? <br />
<br />
<strong>Dr. Atkins:</strong> <br />
Ipilimumab enables an immune response and antitumor responses in some individuals. This agent is powerful enough to work in the central nervous system and overcome concurrent immunosuppression. The response to ipilimumab may be associated with autoimmunity. Activity of the drug is seen in patients previously treated with IL-2. This drug is an option for most patients with advanced melanoma. Optimal timing of therapy and severe autoimmune toxicities should be considered. We don't know the answers to all of the questions about how to use ipilimumab. Should it be combined with dacarbazine? Should it be used as first-line or second-line treatment? What is the optimal dose and schedule? Does it have a role in maintenance therapy? What is its role in the adjuvant setting? What combinations should be studied? Some possible combination partners are bevacizumab, GM-CSF [granulocyte-macrophage colony-stimulating factor], high-dose IL-2, and the novel PD-1 antibody. PD-1 Inhibitor: New Kid on the Block Medscape: At the 2012 annual meeting of ASCO®, we heard exciting preliminary reports about a second checkpoint inhibitor called MDX-1106, a PD-1 antibody.<br />
<br />
How does this immunotherapy work, and what are preliminary observations?<br />
<br />
<strong> Dr. Atkins</strong>: <br />
On activated T-cells, PD-1 serves as the receptor for PD-L1, which is expressed on tumor cells. When PD-L1 binds to PD-1 inside the tumor microenvironment, it paralyzes T-cell immune function. Blocking the interaction between PD-L1 and PD-1 with an antibody provides a specific way to activate the immune system within the tumor microenvironment. It is hypothesized that this would provide a less toxic and more potent means of activating the immune system. Several presentations at ASCO® on this novel immunotherapy showed exciting preliminary results. A large phase 1 study evaluated MDX-1106 given every 2 weeks for up to 2 years in patients with melanoma, renal, and non-small cell lung cancer.[6] Durable responses were seen in all 3 malignancies. In the melanoma patients, about half had tumor shrinkage and some responses were quite significant. This novel therapy will move forward in clinical development for patients with melanoma, either as a single agent or in combination. A number of PD-1 and PDL-1 blockers are under development. Which Patients Are Right for Immunotherapy? <br />
<br />
<strong>Medscape:</strong> How do you select patients for treatment with immunotherapy?<br />
<br />
<strong> Dr Atkins:</strong> Patients with metastatic melanoma are not all the same. There are 2 basic phenotypes: noninflamed and inflamed. Data suggest that the second phenotype is associated with a better prognosis; that is, the greater the percentage of immune cells within a tumor, particularly CD8+ T cells, the better the prognosis. As mentioned previously, patients with tumors expressing an immune signature are more likely to respond and to exhibit a longer progression-free survival than those with tumors that do not have this signature. Studies suggest that PDL-1 expression appears to be associated with benefit, because patients without PD-L1 expression were less likely to respond to PD-1 antibody.[6-8] Sequencing: Which Therapy, and When? Medscape: What is the current thinking on sequencing of therapies? Dr Atkins: In addition to immunotherapies, several new targeted therapies are on the horizon. Vemurafenib, which targets tumor containing a BRAF V600E mutation, is approved for the treatment of patients with metastatic melanoma, and other BRAF and MEK inhibitors are being studied. These therapies may be able to be used in combination with immune therapies to improve outcomes. Most patients would like a chance to be cured. Immune therapies are the only curative therapies for advanced melanomas. Thus, if patients can receive an immune therapy, it may be better to give it first. For BRAF wild-type tumors (those without the BRAF V600E mutation) and even for the BRAF-mutated tumors, it might make sense to give patients an immunotherapy first to try to produce long-term benefit and reserve the use of a BRAF inhibitor for those patients who don't respond to immunotherapy. Data suggest that giving an immunotherapy first does not reduce the ability to respond to a BRAF inhibitor. On the other hand, patients who progress on vemurafenib do not appear to respond to ipilimumab. In fact, in a small study of 32 patients whose disease progresses on vemurafenib, 50% were dead within 4 months.[9] Only 3 of the 32 patients were alive longer than 1 year, and all of them were back on a BRAF or a MEK inhibitor. These preliminary data suggest that a BRAF inhibitor may not be the best initial therapy for some, if not most, patients with BRAF V600E mutations. A prospective trial is needed to study this question. A sequencing study is being planned by ECOG that has 2 arms: ipilimumab with crossover to vemurafenib at time of progression vs vemurafenib with crossover to ipilimumab at time of progression. The primary endpoint will be overall survival at 2 years. The study should tell us which is the best initial therapy for patients with BRAF mutant metastatic melanoma. <br />
<br />
More Work to Be Done <strong>Medscape:</strong> Are there any potential downsides to combining immunotherapy and targeted therapy? <br />
<br />
<strong>Dr Atkins:</strong> By combining immunotherapy and targeted therapy, the hope is to get the benefits of both worlds. But there are potential problems. Studies suggest that dacarbazine interferes with the immune effects of ipilimumab; however, preliminary data suggest that BRAF inhibitors might increase immune infiltration into tumors, converting the microenvironment from a noninflamed state to an inflamed state. Theoretically, this might mean that the combination of a BRAF inhibitor with immunotherapy might produce synergistic antitumor benefits. Medscape: What can you say to sum up where we are with melanoma immunotherapy in 2012? Dr Atkins: We have IL-2 and ipilimumab, and there are novel immunotherapies on the horizon, including the PD-1 antibody. We will need studies to refine optimal patient selection and identify the best combination treatments, including a BRAF inhibitor either alone or in combination with MEK inhibitors. The field has advanced, and in 2012 it is no longer futile to treat metastatic melanoma. There is a glimmer of hope on the horizon, but there is still a lot of work to be done. <br />
<br />
<strong>Source:</strong> <a href="http://www.medscape.com/viewarticle/766473?src=mp&spon=38">http://www.medscape.com/viewarticle/766473?src=mp&spon=38</a> <br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
<br />
~Charles Darwin~ <br />
<br />
Take Care, <br />
<br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-75494787642275530872012-07-03T15:19:00.000-04:002012-07-03T16:10:02.661-04:00Trying to take the guess work out of finding the correct immunotherapy for Melanoma Patients.Jim BreitfellerAs a stage IV survivor/researcher of Melanoma, I know first hand how it feels to be diagnosed with stage IV cancer. You, your family and your caretaker becomes overwhelmed by the information that must be absorbed and processed to make an educated decision on what therapy you want to try. Don’t get me wrong, your oncologist will play a major in your decision, but is it the right one? Is he trying to fill some of his clinical trials or is he looking out for your best interest? Armed with the right information, one can make the best possible choice. It shouldn’t be a hit or miss approach because with cancer, time is of the essence. Getting to the right therapy before you end up at the late stage IV of your disease is the name of the game.
In my therapy, that was my goal, find the right therapy before it overcomes your internal organs and kills you. So, in 2005, I asked my doctor John M Kirkwood if they would take my tumors and biopsy them for gene analysis. Back in 2005, this analytical activity was revolutionary and not done as a standard of care.
So in 2005, I contacted Arlet Alarcon from the Molecular Profiling Institute. I tried to convince Dr. John M. Kirkwood, but it was not to be. But now to fast-forward to 2012 and you will see molecular profiling your tumor becoming common practice.
So with this in mind, here are some suggestions to get you on the right path.
1.) Assemble a team of doctors that specialize in your cancer.
2.) Make sure they see you as a major part of the team and the decision making.
(Be your own advocate)
3.) Learn the medical language so you can research and stay abreast of the new therapies that are being discovered daily.
4.) Learn how your immune system works and how the therapies interact with the immune system.
5.) Be POSITIVE!!!
<br>
Here is the latest slide from "Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy" by Dr. Ribas
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_YcvoygRQj2JxrRSFOtDcCLpsSiHAdslcfBCMx451zaRb_lIoJMD290kBTzqujXpEnLvUo6xB4XS-DHH6MprlZwEnMHaqLkZKwjGFfkQixbL3LePvrCWAYHjV7fe9qMIhyphenhyphenNVZte5fQd0/s1600/treatment+of+advanced+melanoma+in+2012.jpg" imageanchor="1" style="margin-left:1em; margin-right:1em"><img border="0" height="266" width="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_YcvoygRQj2JxrRSFOtDcCLpsSiHAdslcfBCMx451zaRb_lIoJMD290kBTzqujXpEnLvUo6xB4XS-DHH6MprlZwEnMHaqLkZKwjGFfkQixbL3LePvrCWAYHjV7fe9qMIhyphenhyphenNVZte5fQd0/s400/treatment+of+advanced+melanoma+in+2012.jpg" /></a></div>
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permission granted from Clinical Care Options – Oncology
http://www.clinicaloptions.com/oncology.aspx
SOC= Standard of Care
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqFdg9PvC2z8Q6YQJ0uBjZSjPgj2hTXTdPIzmdyfDb2JylCqkyueMhHRbByBMguNRfSELdcIb6uQVwHLnXtQttqIWnpQyrhFAt5bE1NO1Ggg87mU4wFhlUaSmSSCA9gKWX9ImEep8NOqM/s1600/immunotherapy+tumor+growth+curve+2012.jpg" imageanchor="1" style="margin-left:1em; margin-right:1em"><img border="0" height="271" width="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqFdg9PvC2z8Q6YQJ0uBjZSjPgj2hTXTdPIzmdyfDb2JylCqkyueMhHRbByBMguNRfSELdcIb6uQVwHLnXtQttqIWnpQyrhFAt5bE1NO1Ggg87mU4wFhlUaSmSSCA9gKWX9ImEep8NOqM/s400/immunotherapy+tumor+growth+curve+2012.jpg" /></a></div>
What I am trying tell is that by optimizing your personal therapy, you can extend your survival.
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view¤t=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" border="0" alt="Photobucket"></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-15348585583461665012012-06-18T11:02:00.000-04:002012-06-18T14:32:51.531-04:00ACTION! Help Save the Life of Darcy Doherty, Father of Three Children to get immunotherapy drug for melanoma..Jim BreitfellerACTION! Help Save the Life of Darcy Doherty, Father of Three Children to get immunotherapy drug Anti-PD-1 (BMS-936558) for melanoma.<br />
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<br />
Please write to Dr. Elliot Sigal at Bristol Myer Squibb<br />
<a href="mailto:Elliott.Sigal@bms.com">Elliott.Sigal@bms.com</a><br />
<br />
Dr. Sigal is the Director of Research at BMS.<br />
Please send a note to Dr. Sigal requesting that BMS open compassionate use for Mr. Doherty. I know it is a long shot/ Hail Mary Pass but, base on my research, this drug with the combination of IL-2 may be able to beat the odds.<br />
<br />
Bristol Myer Squibb says <strong>"At Bristol-Myers Squibb, we are firmly focused on our Mission to discover, develop and deliver innovative medicines that help patients prevail over serious diseases."</strong><br />
<br />
<strong>Is this all lip service? Let see if BMS puts their money where their mouth is and grant this compassionate care use for this derserving family. Doherty with his clinal trial of Yervoy (Anti-CTLA-4 therapy) helped get the drug FDA approved through his survival data. The least Bristol could do is to grant the dying man compassionate use of the next generation drug called Anti-PD-1, (</strong><strong>BMS-936558)</strong><br />
<br />
<strong>Bristol-Myer Squibb needs to show some compassion.</strong><br />
<br />
<strong>It is their ETHICAL Responsibility.</strong><br />
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<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
~Charles Darwin~<br />
Take Care, <br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-44718948582530046282012-06-17T16:57:00.000-04:002012-06-17T19:12:03.268-04:00A very Happy Father's Day from a stage IV Melanoma Survivor..Jim BreitfellerI want to thank all the people that has made this day a very special Day.<br />
<br />
<br />
As a stage IV Melanoma Survivor, I never dreamed that I would be here today to witness my children spread their wings and learn to fly. My daughter was just entering college when I was first diagnosed and my son, Chris was a sophmore in High School. Today, I am preparing to help my son relocate to Connecticut. He just landed an engineering job at an areospace company. My daughter, Jessica is globe-trotting around the world working on her dual Masters in "International Affairs" and "Natural Resources & Sustainable Development". This day, marks Dee and I as offically "Empty Nesters".<br />
<br />
This all was made possible by entering a journey that entailed four clinical trials along with the best and internationally renowned medical team that makes climbing Mt. Everst apiece a cake. And you , My carepage friends that kept me on the "<strong>Yellow Brick Road".</strong> I have won the "lottery of life."<br />
<br />
Many Thanks<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
~Charles Darwin~ <br />
<br />
Take Care,<br />
<br />
Jimmy B<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-61840627308790819962012-06-11T10:59:00.000-04:002012-06-11T11:09:42.174-04:00Dying man fights to get experimental drug from Bristol-Myers Squibb..Melanoma ..Jim BreitfellerEmily Jackson Staff Reporter Darcy Doherty’s last chance at life lies in an experimental drug. The yet-to-be-approved treatment is the only option left for the 48-year-old father of three with metastatic melanoma, believes his oncologist Dr. David Hogg, an attending physician at Princess Margaret Hospital. But maker Bristol-Myers Squibb (BMS) refuses to give Doherty the drug, saying it’s not yet safe for use outside the clinical trial, which Doherty was excluded from because of new cancer growth in his brain. That reason is simply not good enough for Doherty’s family and friends. If he will certainly die without the drug, why not let him try it? “They have an ethical responsibility to try to save a life,” his wife Rebecca Cumming said as she handed out “Help Save Darcy” stickers at the Ride to Conquer Cancer Sunday. “I think they’re afraid it will be harder to get the drug to market if the drug brings harm to patients like Darcy.” About 30 family friends were at the fundraiser to promote a change.org petition pressuring BMS to give Doherty access to the drug by Father’s Day. Wait much longer, Cumming said, and it will be too late. More than 171,000 have signed the plea. “We love our dad very much and we want a lot more time with him,” Doherty’s emotional 13-year-old son Ganden said in a video. A cancerous mole was first removed from Doherty’s back in 2003. By 2007 the cancer spread to his brain. He survived because of a then-experimental drug. His doctor said immune system off-switch blocker BMS-936558, which has had success in phase one of testing, could have similar benefits. BMS is aware of the petition, but did not budge on its decision. The company empathizes with patients who have limited treatment options, said spokeswoman Sonia Choi in a statement Sunday. Compassionate use requests are carefully reviewed using information from a patient’s physician, she said. To get access, the benefits must outweigh the risks. “At this time, there are not enough data on BMS-936558 to allow its use outside of a clinical trial.” Choi could not provide a timeframe on when more data might become available. The trial’s final stages are set for later this year or early 2013. “In the long term, the best way to ensure the broadest access for patients is to successfully register a medicine with health authorities through the conduct of well-controlled clinical trials.” “There’s no obligation on the drug companies to provide compassionate relief,” said Bernard Dickens, professor emeritus of health law and policy at the University of Toronto. BMS “can’t invest money in handing out unproven products if they’re not going to get data for study purposes.” But if the drug wasn’t safe enough to test on humans, it would not go to stage-two testing, argued advocate Frank Burroughs, founder of American organization the Abigail Alliance for Better Access to Developmental Drugs. For now, Doherty tires quickly. Sitting in his wheelchair at the fundraiser, the former big-bank financial services managing director called the petition an “amazing show of the human spirit.” He thinks it’s “kind of crazy” that he can’t get the drug. “It doesn’t hurt to give a guy a chance.” Source:http://www.thestar.com/news/article/1209218--dying-man-fights-to-get-experimental-drug-bristol-myers-squibb-won-t-give-him We have seen this type of action numerous times with BMS.They did this with Yervoy in the early days, closing compationate use. They appear to have no compassion or ethics, Just Greed!!!! to make a buck. I believe Bristol Myer Squibb is doing a disservice to the Cancer Community especially the Melanoma Patients.<br />
<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=Scrooge-1.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/Scrooge-1.jpg" /></a><br />
<br />
<br />
<strong>"What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life."</strong><br />
<br />
There is no commitment to patients with stage IV Melanoma.<br />
<br />
<strong>They have dollars Signs in the eyes and don't give a cr%& about the patients</strong>.<br />
<br />
This is what Big Pharma has become. <strong><span style="font-size: 180%;"><span style="color: red;">(Greed)</span></span></strong><br />
<br />
Take Care,<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
<br />
~Charles Darwin~<br />
<br />
Take Care, <br />
<br />
Jimmy B<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com1tag:blogger.com,1999:blog-836586378132117060.post-3082209392916078592012-06-06T18:49:00.001-04:002014-05-04T10:48:25.699-04:00Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid Melanoma tumors: Clinical activity, safety, and a potential biomarker for response.Melanoma ..Jim Breitfeller<br />
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I have been following this new treatment for a number of years and am trying to get my arms around the science. <br />
<br />
When a T-cell is activated, the PD-1 , CTLA-4, ICOS, and others molecule are expressed and upregulated to the surface of the T-cell. Both PD-1 and CTLA-4 are checkpoint molecules that regulate the immune response. They are inhibitory to the point that they can shut down T-cell activation. ICOS on the other hand is a costimulatory molecule that is needed, along with IL-2 to keep the T-cell activated and help proliferate the T-cells.Elevated levels of ICOS mRNA can be detected already one hour after TCR engagement, followed by surface expression within 12 hours. Protein expression reaches a maximum after 48 hours and declines then slightly.<br />
<br />
It has been shown that ICOS is inducible within 48 hours of T cell activation on both CD4+ and CD8+ cells after CD28 signaling whereas cytotoxic T lymphocyte antigen-4 (CTLA-4) ligation prevents its upregulation. <br />
<br />
First, CTLA-4 engagement on resting T-cells was found to indirectly block ICOS costimulation by interferring with the signals needed to induce ICOS cell surface expression. Second, on preactivated cells that had high levels of ICOS expression, CTLA-4 ligation blocked the ICOS-mediated induction of IL-4, IL-10, and IL-13, suggesting an interference with downstream signaling pathways. The addition of IL-2 not only overcame both mechanisms, but also greatly augmented the level of cellular activation suggesting synergy between ICOS and IL-2 signaling.<br />
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So after T-cell Activation, IFN gamma is secreted (30 minutes), then IL-2 is secreted (45 minutes in) and so on,<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEic1zzRknDTi4oU4aK_Lvwc7mZn8P35hNgzz1eDUpqTG7vAARrUMzzmqQ1fHShNgw4iWXVQRGAq9q2FInv5FOnlb-uTEgCveMZJa_GJxenD45lvE6j_HRpMdxdcQa1_MTRFusDpzxnbmlM/s1600/T-cell+activation+6-5-12.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" fba="true" height="270" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEic1zzRknDTi4oU4aK_Lvwc7mZn8P35hNgzz1eDUpqTG7vAARrUMzzmqQ1fHShNgw4iWXVQRGAq9q2FInv5FOnlb-uTEgCveMZJa_GJxenD45lvE6j_HRpMdxdcQa1_MTRFusDpzxnbmlM/s640/T-cell+activation+6-5-12.jpg" width="640" /></a></div>
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<br />
The surface expression of ICOS is within 12 hours of activation. Since CTLA-4 blocks ICOS costimulation, Yervoy (anti-CTLA-4) must be used to counter the surpressive signalling. PD-1 also upregulates to the surface in the early activation process. PD-1 is upregulated within 24h after T cell activation.<strong>PD</strong>-<strong>1</strong>-Mediated Suppression of <strong>IL</strong>-<strong>2</strong> Production Induces CD8+ T Cell <b>...</b> <span class="ft">anergy was associated with a marked <strong>down</strong>-<strong>regulation of IL</strong>-<strong>2.</strong></span><br />
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Blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in significant enhancement of proliferation and cytokine (gamma interferon [IFN-gamma] and interleukin-2 [IL-2] secretion by tumor-specific CTLs. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Tregs.<br />
<br />
PD-1 blockade seem to augment the proliferation of the CD4+ helper cells.<br />
<br />
Now you know why just using Anti-PD1 and or Yervoy as a monotherapy will not have a large response rate. Combinational Therapy is a must if we are to see synergistic responses. IL-2 also plays a major roll in the immune response. IL-2 is added to help maintain fuctionality and survival of the Cytotoxic T Lymphocytes (CTLs) that is despartly needed to eradicate the Melanoma tumors. Our immune system can cure cancer, I am living proof of it.<br />
<br />
Jimmy B<br />
<br />
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“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
~Charles Darwin~ <br />
Take Care,<br />
Jimmy B <br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-15567568620355404032012-06-02T16:38:00.000-04:002012-06-02T20:35:14.402-04:00Promising New Approach To Treating Cancer Means Hope For Many, But Remember This Is Just The Start Of The Journey..Melanoma ..Jim BreitfellerPromising New Approach To Treating Cancer Means Hope For Many, But Remember This Is Just The Start Of The Journey<br />
<br />
<a href="http://www.cancer.org/AboutUs/DrLensBlog/post/2012/06/02/Promising-New-Approach-To-Treating-Cancer-Means-Hope-For-Many-But-Remember-This-Is-Just-The-Start-Of-The-Journey.aspx">http://www.cancer.org/AboutUs/DrLensBlog/post/2012/06/02/Promising-New-Approach-To-Treating-Cancer-Means-Hope-For-Many-But-Remember-This-Is-Just-The-Start-Of-The-Journey.aspx</a><br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhR4vqb77H1T0kQW2b6QzvYun2djQbotE8e6dlFjFg1hc5hKTnseT0tsf3LVIbG4N_N6OZQeElITmMzVBbSmTHZItxhEmuKjy9_Byk41BRI_29mOnQX2sIXx8W11Va3fpJsbBhBHzRPrHk/s1600/unlock+the+immune+response+with+Yervoy+and+Anti-PD-1+12-28-2011.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="248" rba="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhR4vqb77H1T0kQW2b6QzvYun2djQbotE8e6dlFjFg1hc5hKTnseT0tsf3LVIbG4N_N6OZQeElITmMzVBbSmTHZItxhEmuKjy9_Byk41BRI_29mOnQX2sIXx8W11Va3fpJsbBhBHzRPrHk/s320/unlock+the+immune+response+with+Yervoy+and+Anti-PD-1+12-28-2011.jpg" width="320" /></a></div>
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<br />
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<br />
A while back , in 2011 I wrote about combinatorial therapy as the way to form a curative therapy for melanoma.See blog entry "“Schedule and Dose for Combination Therapy,”<br />
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<br />
<br />
<br />
It is now just starting to gain acceptance in the oncology world ASCO 2012. You need to block multiple pathways to shutdown the tumor's ability to side-step the immune system.If you search on my blog using the search field, you will be able to follow the science. <br />
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<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgbw3p9-2TPYVwyvF7fsG2PzIkCgwEohBqipygQD8Ga_at9Nk5jJsVyJihwJ2uajc_DcUTDgQLdUDAkzKxWC_q76V3CTPH47ojjdWE-hZRpk4eFb_AQa5wT5Bjc0umnzwY8gCsdP7w2cTU/s1600/The+ultimate+fate+of+cellular+immune+responses+2012.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="148" rba="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgbw3p9-2TPYVwyvF7fsG2PzIkCgwEohBqipygQD8Ga_at9Nk5jJsVyJihwJ2uajc_DcUTDgQLdUDAkzKxWC_q76V3CTPH47ojjdWE-hZRpk4eFb_AQa5wT5Bjc0umnzwY8gCsdP7w2cTU/s320/The+ultimate+fate+of+cellular+immune+responses+2012.jpg" width="320" /></a></div>
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<br />
<br />
<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
<br />
~Charles Darwin~ <br />
<br />
Take Care, <br />
<br />
Jimmy B<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-73426085289720037982012-05-11T12:44:00.000-04:002012-06-02T20:09:23.473-04:00Immunotherapy of cancer in 2012..Melanoma ..Jim BreitfellerThis is a great summary of Immunotherapy as we know it today. A must read for cancer patients, caregivers, Oncologists.<br />
<br />
Download it today!!!<br />
<a href="http://onlinelibrary.wiley.com/doi/10.3322/caac.20132/full">Melanoma Immunotherapy of cancer in 2012</a> <br />
<br />
It is somewhat technical but should be in the patient's, caregiver's and Oncologist's library. Knowledge is power. Power to heal ones disease.<br />
<br /><br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
<br />
~Charles Darwin~<br />
<br />
Take Care, <br />
<br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com1tag:blogger.com,1999:blog-836586378132117060.post-35107819208904584172012-05-03T09:47:00.000-04:002012-05-03T09:47:27.043-04:00An enzyme called tryptophan 2,3-dioxygenase or (TDO) enables tumors to avoid detection and rejection by the immune system..Melanoma .Jim Breitfeller<strong><em><span style="color: #cc0000;">An enzyme called tryptophan 2,3-dioxygenase or (TDO) enables tumors to avoid detection and rejection by the immune system </span></em></strong><br />
<strong><em><span style="color: #cc0000;"></span></em></strong><br />
<strong><br /><em><span style="color: #cc0000;"></span></em></strong><br />
<br />
<br />
NEW YORK, NY, May 3, 2012 – The Ludwig Institute for Cancer Research (LICR) announced today the launch of a private biotechnology enterprise, iTeos Therapeutics SA, to develop a novel pre-clinical pipeline of immunomodulators to stimulate the immune system's ability to attack cancer<br />
<br /><br />
iTeos co-founder and CEO Michel Detheux, Ph.D. "<strong><u><span style="color: red;">We now know that combination treatments are likely to be more effective than single therapies in controlling and eventually eliminating cancer</span></u></strong>. iTeos will pursue this approach by combining existing vaccines with new immunodulatory compounds based on research that has just emerged from the Ludwig Institute."<br />
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<strong>Cancer immunotherapy </strong><br />
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— leveraging the body’s own immune system to attack and destroy tumors — is emerging as a promising method for cancer treatment. Clinical testing of several immunotherapeutic approaches has shown variable success. Tumors often develop survival mechanisms to prevent the attack from the immune system. Researchers are now looking to evaluate the mechanisms that enable these tumors to escape detection by the immune system.<br />
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Previously, Brussels scientists from LICR and the de Duve Institute at the Université catholique de Louvain (UCL) studied one enzyme that proved to do just that. It is known as indoleamine 2,3 dioxygenase or IDO1 for short. IDO1 is expressed in many cancers, including prostate, colon, pancreas and cervical tumors. IDO1 blocks the immune system’s ability to reject those tumors, by depriving immune cells of tryptophan. Tryptophan is one of the essential amino acids for the body.<br />
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Tryptophan is an amino acid needed for normal growth in infants and for nitrogen balance in adults. It is an essential amino acid, which means your body cannot produce it -- you must get it from your diet.<br />
<br />
Tryptophan can be found in:<br />
<br />
• Cheese<br />
•Chicken<br />
• Eggs<br />
• Fish<br />
• Milk<br />
• Nuts<br />
• Peanut butter<br />
• Peanuts<br />
• Pumpkin seeds<br />
• Sesame seeds<br />
• Soy<br />
• Tofu<br />
• Turkey<br />
Scientists from the Ludwig Institute for Cancer Research (LICR) in Brussels identified a new target for cancer therapy, an enzyme which prevents the immune system from recognizing and destroying certain types of tumors. Called tryptophan 2,3-dioxygenase or TDO, the enzyme works by depriving immune cells of tryptophan, an amino acid essential to their activity. TDO is produced by a significant number of human tumors including melanomas.<br />
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The Ludwig Institute is now applying this knowledge and now is investigating inhibitors of these two enzymes (IDO and TDO).<br />
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“Little is known about the TDO enzyme and its ability to trick the immune system and prevent it from destroying deadly tumors” said study lead investigator, Benoit J. Van den Eynde, M.D., Ph.D., Brussels Branch Director at LICR.<br />
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The (Belgium) team of scientists then developed an active compound to inhibit TDO enzymatic activity. “Our study showed quite beautifully that the TDO inhibitor restored the ability of mice to reject tumors despite the presence of TDO in tumor cells,” said Dr. Van den Eynde<br />
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Cancer research is like analyzing an onion; you pull one layer off at a time and discover another layer of suppression from the tumor’s microenvironment. We are forever gaining knowledge about the immune system. <strong><span style="color: red;">The CURE will come from Combinatorial Therapy!!!</span></strong><br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
~Charles Darwin~<br />
Take Care, <br />
<br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-86273785820366974232012-05-02T16:03:00.001-04:002012-06-02T20:10:10.490-04:00Complexities of cancer elude magic bullet..Melanoma ..Jim Breitfeller<strong><span style="color: blue;">Complexities of cancer elude magic bullet</span></strong><br />
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<br />
"True change will entail extending survival not by months, but by years, moving ever closer to the five-year cancer-free mark that is considered a cure. Unfortunately, this remains an elusive goal for many types of cancer due to the near inevitability of recurrence.<br />
The reasons for this are many and controversial, but few dispute that the problem lies in the complexity of cancer, the growth and metastasis of which involve multiple processes, pathways and cell types. Because most drugs target only one of the many factors that give rise to cancer, it is not surprising that the disease so commonly displays an aptitude for evading them.<br />
Given cancer's complexity, most agree that the long-coveted cure will be found not in a magic bullet, but in a combination of bullets aimed simultaneously at several specific targets. Here, immune-based drugs present a number of distinct advantages: their favorable safety profile is conducive to combination therapy, and a number of different immunotherapy candidates have shown promising activity against well-established tumor targets.<br />
However, because the U.S. Food and Drug Administration requires each of these experimental treatments to be tested individually, it is far from clear that any of these products alone could pass the demanding test of significantly improving overall survival - even if there is good reason to believe that they could provide significant benefit together. " ~Swiss Trader~<br />
<br />
<strong>We need the FDA to consider Combinatorial Therapy as a new Product/Process that is capable to win this war on Cancer.</strong><br />
I have lived it first hand, and have benefited from this form of therapy. It was no fluke that I was able to jump-start my immune system. With the help of my Oncologist we were able to string the right clinical trials together to produce the right immune response. Some day we will all look back to this day and say to ourselves, why did no one take notice. <br />
The <span style="color: red;"><strong>CURE</strong></span> is right under our noses. Think outside the box!<br />
<br />
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjux62E-pVGVK_NPUE7ziTuQ_x_IV_PrFFxrKKaYXS616OIwLQ-oxOHpqH8NUL7muVd1E6wrWiAJ8nry6cMOgg4C1yBhqQ2X01vb1GUnavoDHVSMKVV2-x0Yrz3xNDPZRqaWHVUG7GqyU/s1600/The+ultimate+fate+of+cellular+immune+responses+2012.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="148" mea="true" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjjux62E-pVGVK_NPUE7ziTuQ_x_IV_PrFFxrKKaYXS616OIwLQ-oxOHpqH8NUL7muVd1E6wrWiAJ8nry6cMOgg4C1yBhqQ2X01vb1GUnavoDHVSMKVV2-x0Yrz3xNDPZRqaWHVUG7GqyU/s320/The+ultimate+fate+of+cellular+immune+responses+2012.jpg" width="320" /></a></div>
<br />
<br />
Best regards,<br />
<br />
Jimmy B<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
~Charles Darwin~ <br />
Take Care, <br />
Jimmy B<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-50746541769338827512012-04-29T11:58:00.001-04:002012-04-29T11:58:59.905-04:00Giving Thanks… Five Years Later..Melanoma..Jim BreitfellerGiving Thanks… Five Years Later<br />
<br />
Back in July of 2005 I was diagnosed with Melanoma Cancer. It has turned my life inside out and upside down. Here is a note that I sent to my colleagues at Eastman Kodak. <br />
<br /><br />
<em>Dear Friends and Family,</em><br />
<em><br /></em><br />
<em>I wanted to take a moment to let you know that I’ll be leaving my position at Eastman Kodak Company as of March 9, 2007. I will be starting a new phase of my life trying to win this battle of cancer. My short term disability ends and the long term starts.</em><br />
<em><br /></em><br />
<em>I have enjoyed my 25 years there and I appreciate having had the opportunity to work with each and every one of you. Thank you for the support, guidance, and encouragement you have provided me during my time at Kodak. Even though I will miss my colleagues and the company, I am looking forward to this new challenge and to starting a new phase of my life. Even though the paths are many, I must go down each one to find the “Yellow Brick Road.” With your support and encouragement we can beat this disease together.</em><br />
<em><br /></em><em>Please keep in touch,</em><br />
<em><br /></em><br />
<em>Jimmy B</em><br />
<br /><br />
It has been five years now and I believe I accomplished what I had set out to do, that was to beat this disease melanoma. With the help of family, carepage friends and researchers, oncologists, we have come a long way. I have spent most of my waking hours researching and helping fellow melanoma comrades traverse the canyons of this disease. Along the way I have met and lost so many friends to this disease and only wish that they could be here today to celebrate with me.<br />
<br />
<br />
<br />
Without you, I would not have been so focused on finding a cure. So today , I just want to say thanks for everything. Thanks for keeping me on the right path and believing in me. We are making great inroads in understanding the immune system and how it can be trained to eradicate Cancer. <strong>We are in the emergence of the renaissance (</strong>A rebirth) <strong>of Immunology and Combinatorial Therapy. I believe whole heartedly that we will see a Cure for cancer in my lifetime.</strong> <br />
<br />
We must keep on persevering to obtain that goal.<br />
<br /><br />
Jimmy B<br />
<br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.” <br />
<br />
~Charles Darwin~ <br />
<br />
Take Care, <br />
<br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-49185334064330454502012-04-27T12:27:00.000-04:002012-04-28T17:09:45.924-04:00Macrophage Activation… The Missing Link to Activation an immune response to Melanoma..Jim Breitfeller<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhccv3r7tb-ul5ySL7LFZA1gvZzh7Jv7WqhpB41b1YXGYx7tVzchHQvPtaseNCi08CYGJpChPBlFvueZO1mSbUKbd0Dllk_hfHtB9Jr9EFqVAtacZyzIuLSCvyk3MwEl12AeBfSUQ_KHoQ/s1600/Macrophage+Activation+2012.jpg" imageanchor="1" style="margin-left:1em; margin-right:1em"><img border="0" height="400" width="378" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhccv3r7tb-ul5ySL7LFZA1gvZzh7Jv7WqhpB41b1YXGYx7tVzchHQvPtaseNCi08CYGJpChPBlFvueZO1mSbUKbd0Dllk_hfHtB9Jr9EFqVAtacZyzIuLSCvyk3MwEl12AeBfSUQ_KHoQ/s400/Macrophage+Activation+2012.jpg" /></a></div><br>
"The development of Th1 cells producing high levels of IFN-gamma could not be induced with dendritic cells alone but required the addition of appropriately activated macrophages."
Et al A. O'Gara March 23, 1993 "Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from αβ TCR transgenic mice: IL-12 substitution f.or macrophages to stimulate IFN-γ production is IFN-γ-dependent"<br>
Local IL-12 therapy stimulates Th cells to secrete Th1 cytokines. Exogenous IL-12 application creates an environment rich in IL-12 around the cancer site. In such a local environment, newly activated Th cells, responding to the presence of cancer, exit the blood and are influenced to become Th1 cells and secrete more Th1 cytokines and activate macrophages and NK cells. Activated macrophages will produce more IL-12 and via positive feedback, cell-mediated immunity can be promoted to battle the cancer thereby leading to the prevention of reoccurrence.
As you can see, the activated macrophage secretes IL-12, IL-1a, IL-1b, and IL-6 along with a Chemoattractant, IP-10. Without macrophage activation, the immune response does not take place and the patient will relapse.(see graphic below)
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEioTXcWNSNgCg61hddY9fa83sm-W3KQpYgkqruLFOs5aOGtVuGA14QUBICnEPrtaemeLiRKskicULPr2uL3IEhYvT7mQqFMSNcncUXzyv17v9Wqvvnzw3VsdoL1J_XOORPzuwwyYJvKks8/s1600/Missing+Cytokines+%2528Low%2529.jpg" imageanchor="1" style="margin-left:1em; margin-right:1em"><img border="0" height="400" width="352" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEioTXcWNSNgCg61hddY9fa83sm-W3KQpYgkqruLFOs5aOGtVuGA14QUBICnEPrtaemeLiRKskicULPr2uL3IEhYvT7mQqFMSNcncUXzyv17v9Wqvvnzw3VsdoL1J_XOORPzuwwyYJvKks8/s400/Missing+Cytokines+%2528Low%2529.jpg" /></a></div>
With IL-1b and IL-6 missing, the T-Regulatory Cells (Tregs) rule the Tumor's Microenviroment.
IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4+ T cells into Foxp3+ regulatory T cells.
IL-1β–Mediated Signals Preferentially Drive Conversion of Regulatory T Cells but Not Conventional T Cells into IL-17–Producing Cells (Danger Signal).<b>So if the IL-1b signaling is missing,conversion of the Tregs never take place along with no Danger Signals.</b>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimX9j9CuPURMNcTFnrmR1xzoSVTJIeNsrjqKQlDv_wTahW0ECIwc05tsS3XoRXdh5TTEQXqH2Q9JqdWmOiWSOKpwiqe7kHtGBt8YCqx1K3yW6zaqw-CQ5kYvGfKjJU9ImLWgqDQmpvH1E/s1600/Th17+danger+Signal+2011.jpg" imageanchor="1" style="margin-left:1em; margin-right:1em"><img border="0" height="393" width="400" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimX9j9CuPURMNcTFnrmR1xzoSVTJIeNsrjqKQlDv_wTahW0ECIwc05tsS3XoRXdh5TTEQXqH2Q9JqdWmOiWSOKpwiqe7kHtGBt8YCqx1K3yW6zaqw-CQ5kYvGfKjJU9ImLWgqDQmpvH1E/s400/Th17+danger+Signal+2011.jpg" /></a></div>
Dr. Steven Rosenberg is using engineered T-cells that secrete IL-12 to stimulate Th cells to secrete Th1 cytokines. This sets in motion the positive feed back loop needed to initiate an immune response. His therapy is show great promise.
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B
<br>
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view¤t=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" border="0" alt="Photobucket"></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0tag:blogger.com,1999:blog-836586378132117060.post-44551948760791676032012-04-26T21:56:00.001-04:002012-04-26T21:56:03.600-04:00ESMO 2010: Tumor immunology and combined immunotherapies - Prof Ignacio Melero - University of Navarra, Pamplona, Spain<a href="http://ecancer.org/tv/pubdate/792#.T5nzWBwUCxo.blogger">ESMO 2010: Tumour immunology and combined immunotherapies - Prof Ignacio Melero - University of Navarra, Pamplona, Spain</a><br />
<br />
“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”<br />
~Charles Darwin~<br />
Take Care,<br />
<br />
Jimmy B<br />
<br />
<a href="http://s384.photobucket.com/albums/oo290/jimmy_b/?action=view&current=DonQuixtoteandthewindmills-3.jpg" target="_blank"><img alt="Photobucket" border="0" src="http://i384.photobucket.com/albums/oo290/jimmy_b/DonQuixtoteandthewindmills-3.jpg" /></a>jimmy_Bhttp://www.blogger.com/profile/14256359729117724579noreply@blogger.com0