The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" may be due to an enzyme called IDO

The Missing Link in T-cell activation using a Vaccine, "The Danger Signal" may be due to an enzyme called IDO

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”.

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

This is what I was looking for! 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.

We concluded from these studies that IL-1 and perhaps IL-6 play a critical role in the differentiation and expansion of Th17 cells. Yoshihiro Miyahara et al

 

IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4⁺ T cells into Foxp3⁺ regulatory T cells.

Using in vitro and in vivo approaches, we determined that under neutral conditions, simultaneous activation of Tregs and naive CD4⁺ conventional T cells in the presence of APCs resulted in conversion of Tregs into IL-17–producing cells, and endogenous IL-1β was mandatory in this process according to Vassiliki A. Boussiotis et al. “IL-1β–Mediated Signals Preferentially Drive Conversion of Regulatory T Cells but Not Conventional T Cells into IL-17–Producing Cells”

IL-6 protects CD4 T cells from cell death but also inhibits the suppressive effect of T regs.

“Thus, the addition of IL-6 to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer. The delayed tumor growth and improved survival suggests that induction of Th17 in the tumor microenvironment produces an antitumor effect.” David C. Linehan  et al

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!!

Naïve CD4 T cells in the presence of   TGF-b and IL-2 and others differentiate into Tregs.

TGF-b accelerates the CTLA-4 expression by stimulated CD4+ CD25- T-cells

TGF-b requires CTLA-4 early after T-cell activation to induce FoxP expression generating CD4+ CD25+ Treg  Regulatory cells.

The Th-17 cells produce IL-17. .IL-17 induces the production of many other cytokines (such as IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α)

 

So what was the non-responder missing, IL-6.  With the missing IL-6, they weren’t able to produce Th-17 that secreted IL-17.

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.

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 TNF-α and IL-1β 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

 They were missing “The Danger Signal”.

Friendly inflammation “The Danger Signal”

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.

 “The CD8+ T-cell-mediated Immune Response to Eradicate the Tumors”

 “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. 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. Third, inflammatory cytokines, including IL-1, IL-6, IL-12, IL-17 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.

 

 

 

The responder was able to produce inflammatory cytokines, including IL-1, IL-6, IL-12, IL-17 and IFN-γ provides 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 and invoke a robust immune response to the Melanoma Cancer.

 

 

Conclusion:  Based on my observation, the cytokine that ties this “Danger Signal” to the immune system is IL-6.

• IL-6 protects CD4 T cells from cell death but also inhibits the suppressive effect of Tregs.
• IL-6 controls Th17 immunity by inhibiting the conversion of naive CD4⁺ T cells into Foxp3⁺ regulatory T cells.

So what is causing the lack of IL-6 in the non-responders? The IDO enzyme. This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine.

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.

My guess is the tumor induced enzyme called IDO may the Missing Link to intiating an immune response.IDO produced by Tumor cells significantly inhibited interleukin (IL-2) expression and proliferative response in T-cells and increased apoptosis (death) of T-cells. Tryptophan depletion is known to halt cell cycle progression by triggering the antiproliferative GCN2 pathway in lymphocytes.

Also, IDO is upregulated in antigen-presenting dendritic cells (DC) by autocrine IFN-γ released as a result of T_reg cell–induced CTLA-4/B7-dependent cell-cell signaling.

It is well established that IDO expression by APCs or tumors can inhibit immune responses.

Tryptophan depletion by IDO-expressing tumors is a common mechanism of immune evasion inducing regulatory T cells and inhibiting effector T cells.

So adding IDO inhibitor to a combinatorial therapy like Yervoy for melanoma cancer should see a synergist response.

 

 

 

 

Bristol Myer Squibb and Incyte Corporation are following this Science along
Newlink.

“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

Legislation for Combinatorial Therapy >> Melanoma ..Jim Breitfeller

Congressman 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.

“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

You and Your Doctor—Tackling Your Cancer Together..Melanoma..Jim Breitfeller

You and Your Doctor—Tackling Your Cancer Together

 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.

 Educate yourself


 Visit websites designed to educate and assist patients with your type of cancer.

 Ask your doctor where you can learn more about your cancer, its treatment and any ongoing research.

Be informed when you talk to your doctor and treatment team.

Ask questions and be proactive.

It’s your health—and your life!

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.


Here are some questions you might ask your doctor:

Are there gene mutations identified for my type of cancer?
 Should my tumor be tested for gene mutations?
What can molecular testing tell me about my cancer?
What can molecular testing tell me about my prognosis?
How might molecular testing affect my treatment plan?
How can I get my tumor or biopsy tested?

 “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

 

Anti-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

I have been following this new treatment for a number of years and am trying to get my arms around the science.

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.

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.

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.

So after T-cell Activation, IFN gamma is secreted (30 minutes), then IL-2 is secreted (45 minutes in) and so on,

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.PD-1-Mediated Suppression of IL-2 Production Induces CD8+ T Cell ... anergy was associated with a marked down-regulation of IL-2.

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.

PD-1 blockade seem to augment the proliferation of the CD4+ helper cells.

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.

Jimmy B



“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

New melanoma treatment -- a turning point against cancer? Jim Breitfeller

This is not new!! If you read my paper "Melanoma and the Magic Bullet" from the shared files, you will see that I was able to shed tumor antigens using Chemotherapy.

New melanoma treatment -- a turning point against cancer?

“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

Lloyd J. Old, Champion of Using Cells to Fight Cancer, Dies at 78..Melanoma..Jim Breitfeller

Lloyd J. Old, Champion of Using Cells to Fight Cancer, Dies at 78

My theory on how the immune system works on Melanoma had it's starts with papers from Dr. Lloyd Old.

Lloyd J. Old, Champion of Using Cells to Fight Cancer




“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

Treating Cancer by Targeting the Immune System ..Melanoma ..Jim Breitfeller

Treating Cancer by Targeting the Immune System
Editorial by Dr. Patrick Hwu of MD Anderson

"There is currently great interest in the targeted therapy of cancer. Antibodies that target specific antigens on the surface of cancer cells — such as rituximab, which binds to CD20 on lymphoid tumors, and trastuzumab, which blocks HER2 on breast-cancer cells — were early successes.

However, a novel method of using antibodies to stimulate an antitumor response was pioneered in the mid-1990s by James Allison and colleagues.1
Because the body’s immune response, if left unchecked, can result in autoimmunity, we have evolved a number of immune “checkpoints” that
work as braking mechanisms to counterbalance immune activation. Studies in animals have shown that inhibition of these checkpoints — such as
with an antibody against the cytotoxic T-lymphocyte– associated antigen 4 (CTLA-4) molecule, an inhibitory membrane protein that is expressed after T-cell activation — enhances immune activation against cancer cells, resulting in significant antitumor effects."

Source:Treating Cancer by Targeting the Immune System


https://www.box.net/shared/8rdyaembf6

The Main Take away is:

"Despite dramatic effects in a subgroup of patientsreceiving the anti–CTLA-4 drug, the majority of patients with metastatic melanoma do not
respond to this agent, and further work is vital to improve these results. Future efforts should include the rational combination of anti–CTLA-4 agents or alternative checkpoint inhibitors with targeted therapies or other immune agents. Instead of attempting to marginally increase the median survival, the primary goal of these new combination therapies should be to enhance the percentage of long-term survivors, thereby elevating the “tail” of the survival curve. It should be possible to realize this goal if there is adequate synergy and cooperation among academia, regulatory agencies, and the pharmaceutical industry"

We all need to work together to find the CURE.

Melanoma and the Magic Bullet [Monoclonal Antibodies]


“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

Is a Cure in Sight?Melanoma..Jim Breitfeller

-Melanoma Researchers Striving for New Therapies for Patients-
HILLSBOROUGH, N.J.—The recent debut of “The Big C” on Showtime has placed some of Hollywood’s spotlight on melanoma, the deadliest form of skin cancer. The show features award-winning actress Laura Linney as Cathy Jamison, a middle-aged woman who receives a diagnosis of stage IV melanoma, and the storyline follows her pursuit to enjoy life and find peace in her diagnosis.

Yet “The Big C” bypasses one of the key issues that people with melanoma face – the difficulties in navigating the limited choices in treatment. Linney’s character chooses no treatment, in contrast to the majority of melanoma patients who work tirelessly to find the best therapeutic option for themselves.

In recent years, new drugs have shown promise and these advances give people with melanoma reason to seek out care. “We strongly believe that, unlike Linney’s character, those who have been diagnosed should consider the full range of options that are available to them in fighting melanoma, from surgery to approved treatments and promising clinical trials,” said Tim Turnham, executive director of the Melanoma Research Foundation (MRF).

Progress in expanding options for those with advanced melanoma has received significant media coverage recently, particularly news from the annual meeting of the American Society of Clinical Oncology (ASCO) held in June. A new study was presented that found promising results for those diagnosed with metastatic melanoma, and showed an improved overall survival for the first time in 30 years. There has not been a new drug approved for those with advanced melanoma in over a decade.

Increasingly, scientists and researchers suspect that there is no single drug that will effectively treat melanoma and believe that a combination or “cocktail” of drugs may be the answer to treating advanced melanoma. However, it can be difficult to coordinate clinical trials for drugs.

Is a Cure in Sight?

Melanoma and the Magic Bullet [Monoclonal Antibodies]



Source:http://www.melanoma.org/sites/default/files/press-release/MRF%20Release%20-%20August%20FINAL.pdf


“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

The Perfect Storm..Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo

The Perfect Storm..Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo
Dr. Cassian Yee
Fred Hutchinson Cancer Research Center
Clinical Research
Program in Immunology
Member Appointed: 2009
University of Washington School of Medicine Medicine

Oncology

Associate ProfessorAppointed: 2004
Fred Hutchinson Cancer Research Center
Immune Monitoring Laboratory
Director Appointed: 2003


In my studies, I contacted Dr. Cassian Yee about what I think would revolutionize Melanoma Treatment. Dr. Yee is noted for one of the first Scientists to harness the Immune system to fight Melanoma (2008).

"In what could be a breakthrough in cancer therapy, researchers report in The New England Journal of Medicine today that they succeeded in bolstering a patient's immune system enough to wipe out late-stage malignant tumors on its own. The scientists say the successful experiment could pave the way for new treatments of advanced cancer that spare patients the side effects of chemotherapy, which kills healthy as well as malignant cells."

Source: http://www.scientificamerican.com/article.cfm?id=patient-heal-thyself-body



Dear James,
i have not gone over in detail the information you sent, but i and think others will agree that anti-CTLA4 augments / lowers the threshold for a productive anti-tumor response once that is initiated in some form ('spark'). the role of aCTLA4 and Tregs is still not entirely worked out. I am glad that this has worked out well for you and with the emergence of immunotherapy in general as a treatment modality, with studies coming from Drs. Wolchok, Allison and others, we all hope that the
'Message keeps getting clearer'

Best
Cassian Yee


As you can see by the reply, I think we are onto something big.

I don’t want to waste your time but I think this issue is of the utmost importance. Your Ipilimumab is the major factor in keeping the CD4+ T-cells activated, but it can’t do it alone.



"You need the tumor specific antigens, (The Keys), you need the (Spark Plug) Anti-CTLA-4 and you need the (Gas) IL-2. Without these three key components your car won’t run." ~jimmy B~



As a patient/survivor/researcher of stage IV Melanoma I have scientifically accounted for why my therapy has worked. Above are supporting documents and also a paper (draft) I have written that describes my treatment journey. Please, take time out of you busy schedule and take a look these documents. Bristol Meyer Squibb holds a very promising drug, and when administered in the correct timing and dose, can jumpstart the (Car) The Immune system.

I think they are making great strides in the fight against Melanoma

We need to put it into practice.


“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

This is what is keeping my Melanoma Lesion at bay ..Jim Breitfeller

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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.”

~Charles Darwin~

Take Care,
Jimmy B

Unleashing the Immune System to Destroy Melanoma..Jim Breitfeller

Applying dosing schedules to the clinical protocols of combinatorial therapy, we can optimize the clinical outcome 4-14-2010




The Making of an Immune Response using Anti-CTLA-4 Blockade with Interluekin 2

There is one missing link in all of this. The "DANGER SIGNAL"

How do we generate the Danger Signal so our immune system knows that there are foreign invaders (Melanoma Cancer cells)are present? I have been researching this for quite some time now. I call it the "Missing Link". Bristol Myer Squibb thinks that their Ipilimumab can be used as a monotherapy, but they are mistaken. They want you to believe that their drug is doing all the work but behind the sences there is real Biochemistry taking place. Interluekin-2 is one of the most important players in this Orchestra.

In the next couple of weeks I will elaborate on my theory of the Danger Signal and reveal the pieces of the puzzle that i have discovered in my research.

But for now, let the light shine on Ipilimumab, (anti-CTLA-4 blockade) from Bristol Myer Squibb


“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

The quantal theory of how the immune system discriminates between "self and non-self"..Melanoma..Jim Breitfeller

The quantal theory of how the immune system discriminates between "self and non-self"
Kendall A Smith
2004

If you get a chance to read this paper; You will now know why, the combinatorial therapy of Anti-CTLA-4 Blockade and HD Interluekin-2 will work on jump starting your Immune System.

Please take your time in reading this paper. It could save your Life!!!

"In the past 50 years, immunologists have accumulated an amazing amount of information as to how the immune system functions. However, one of the most fundamental aspects of immunity, how the immune system discriminates between self vs. non-self, still remains an enigma. Any attempt to explain this most intriguing and fundamental characteristic must account for this decision at the level of the whole immune system, but as well, at the level of the individual cells making up the immune system. Moreover, it must provide for a molecular explanation as to how and why the cells behave as they do. The "Quantal Theory", proposed herein, is based upon the "Clonal Selection Theory", first proposed by Sir McFarland Burnet in 1955, in which he explained the remarkable specificity as well as diversity of recognition of everything foreign in the environment. The "Quantal Theory" is built upon Burnet's premise that after antigen selection of cell clones, a proliferative expansion of the selected cells ensues. Furthermore, it is derived from experiments which indicate that the proliferation of antigen-selected cell clones is determined by a quantal, "all-or-none", decision promulgated by a critical number of cellular receptors triggered by the T Cell Growth Factor (TCGF), interleukin 2 (IL2)."
The quantal theory of how the immune system discriminates between "self and non-self"





“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

CTLA-4 blockade with ipi: Long-term follow-up of 179 patients with metastatic melanoma ASCO 2010.Jim Breitfeller

Cytotoxic T lymphocyte-associated antigen 4 blockade with ipilimumab: Long-term follow-up of 179 patients with metastatic melanoma.

The combination of ipilimumab and IL-2 appears to have an increased complete response rate

Meeting: 2010 ASCO Annual Meeting



Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 8544)

Abstract No: 8544
Attend this session at the ASCO Annual Meeting!

Session: Melanoma/Skin Cancers

Type: General Poster Session

Time: Sunday June 6, 8:00 AM to 12:00 PM

Location: S Hall A2

Personalize your Annual Meeting experience with a suggested or customized itinerary!





Author(s): P. A. Prieto, J. C. Yang, R. M. Sherry, M. S. Hughes, U. S. Kammula, D. E. White, C. L. Levy, S. A. Rosenberg, G. Q. Phan; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; National Cancer Institute, National Institutes of Health, Bethesda, MD; National Cancer Institute, Bethesda, MD; Surgery Branch, National Cancer Institute, Bethesda, MD



Abstract:

Background: We have previously shown objective clinical responses in patients with metastatic melanoma treated with CTLA-4 blockade using ipilimumab. We have treated 179 patients in 3 separate clinical trials and now have long-term follow-up to evaluate the durability and unique features of this immunotherapy. Methods: A total of 179 patients with metastatic melanoma were treated in 3 trials: In Protocol 1, 56 patients received ipilimumab with gp100 peptide vaccines. In Protocol 2, 36 patients received ipilimumab with high-dose interleukin-2 (IL-2). In Protocol 3, 87 patients received intra-patient dose escalation of ipilimumab and were randomized to receive gp100 peptides. We have updated and analyzed the follow-up and survival data for these trials. Results: With median follow-up for Protocol 1, 2, and 3 being 80, 71, and 60 months, median survival was 15, 16, and 13 months, respectively. Objective tumor regression was 12% for Protocol 1, 25% for Protocol 2, and 21% for Protocol 3. Patients in Protocol 2 had a 17% complete response rate (6 patients: 77+, 74+, 72+, 71+, 71+, and 69+ months), as compared to 7% in Protocol 1 (4 patients: 82+, 81+, 79+, and 66+ months) and 8% in Protocol 3 (5 patients: 64+, 63+, 62+, 60+, and 55+ months); all complete responses are ongoing. Many patients who eventually became complete responders had continual tumor shrinkage after stopping therapy.

Conclusions: CTLA-4 blockade with ipilimumab can achieve durable objective tumor regression in patients with metastatic melanoma. The combination of ipilimumab and IL-2 appears to have an increased complete response rate, although this needs to be tested in a prospective randomized trial. This report represents the largest single-institution experience with the longest follow-up for this agent; our results support its role as a viable treatment option for patients with metastatic melanoma.


Source:http://www.abstract.asco.org/AbstView_74_53615.html


Cytotoxic T lymphocyte-associated antigen 4 blockade with ipilimumab: Long-term follow-up of 179 patients with metastatic melanoma.


It has taken them two years to see the synergy of Ipi + IL-2

My Theory is becoming a reality!!!!!!!!!!!!!!!
Melanoma and the Magic Bullet





The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2



“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

Smart bombing Melanoma..Jim Breitfeller

Smart bombing Melanoma

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

“Most tumors arise from a single normal cell through a sequential evolutionary process of mutation and selection. Tumors are initiated by escaping non-immune surveillance, which includes defective DNA repair, gene alternation, resistance to apoptosis and loss of intercellular contact inhibition. Tumor cells harbor mutations in a number of critical genes that provide selective advantages at various stages during the evolution of the tumor. The tumor cells that circumvent the tumor suppressor mechanisms of the non-immune surveillance process are edited by the immune system, resulting in the selection of a resistant tumor variant. The selection of the tumor cell is further shaped by its interactions with cells and other factors in its microenvironment. Tumor evolution is thought to adhere to Darwinian principles by escaping both non-immune (intrinsic) and immune (extrinsic) responses against self-altered tumor cells. At end-stage, tumors have escaped both non-immune and immune surveillance with increased threshold of apoptosis. Combination therapy has been proposed, by exploring the non-immune and immune suppressive nature of the tumor, and has been found to have a therapeutic efficiency on tumor regression as compared with monotherapies. The combination of immunotherapy and other different modalities, especially vaccines, with conventional anticancer therapies with optimized dosage and scheduling can offer synergistic antitumor effects.”

Source: http://www.cellbiolint.org

Chemotherapy

The combination of chemotherapy and immunotherapy is synergized as chemoimmunotherapy; chemotherapy can kill or slow the growth of cancer cells and immunotherapy stimulates or restores the ability of the immune system to fight against cancer (Emens and Jaffee, 2005; Gulley et al., 2007). Apoptotic death, particularly massive apoptosis by chemotherapy, can be a priming event for antitumor immunity, allowing the tumors to act as its own vaccine by releasing a large amount of tumor antigen. This priming event sets the stage and the direction of the immune response. With the right tumor antigen, the activated T-cells (CTL’s) Cytotoxic T Lymphocytes can zero in on their target, the tumor cell. Smart bombing Melanoma!!!!!



Source: http://thefutureofthings.com/articles/1012/smart-bombing-cancer.html


Source: NCI



“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

The news Is good!!!!! I am still Stable..Melanoma.. Jim Breitfeller

The news Is good!!!!! I am still Stable

Have I beaten this Beast? Time will only tell. As it gets longer from the day of regression, the better the chance of survival.

I believe that it was the combination of treatments that saved my life.

I just wish the clinical research oncologists would take notice.

My immune system did all the work. I believe I am the first patient to get immunized by my own T-cells. Medical history in the making.



The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2



Take Care,
Jimmy B

Goshen Doctor on Time's 100 List.. Melanoma ..Jim Breitfeller

Goshen Doctor on Time's 100 List

TIME Magazine announced that Dr. Doug Schwartzentruber, Medical Director of Goshen Health System's Goshen Center for Cancer Care, has been named to the 2010 TIME 100, the magazine's annual list of the 100 most influential people in the world

He is being recognized for the strides he and Goshen Center for Cancer Care are making in cancer research.


"One of the first studies to prove vaccines might have a medical benefit against cancer, Schwartzentruber's study results found the new therapeutic cancer vaccine, given in combination with an existing melanoma treatment called Interleukin-2, doubled the response rate for tumor shrinkage as well as delayed the progression of cancer in patients with metastatic melanoma."

Source:http://www.insideindianabusiness.com/newsitem.asp?ID=41419

Goshen Doctor on Time's 100 List 2010


The reason I am brining this to your attention is that I have wrote to
Dr. Schwartzentruber.

The timing of the addition of IL-2 to the vaccine is crucial to the response outcome.

Just think what could be accomplished if Dr.Schwartzentruber timed the addition of the IL-2.



The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2





Take Care,

Jimmy B

Melanoma: A model for testing new agents in combination therapies..Jim Breitfeller

Melanoma: A model for testing new agents in combination therapies

Email to Dr. Mario Sznol 4-27-2010

Dr. Sznol,



I just read your paper on test new agents in combination therapies. I would like you to take a look at a combination that I did as a stage IV Melanoma Patient under the care of Dr. John M. Kirkwood.

Melanoma: A model for testing new agents in combination therapies



It involves interferon alpha, DTIC + Patrin-2 , Anti-CTLA-4 blockade and HD interleukin-2. By doing these drugs in a systematic way, I was able to eradicate 40+ nodules in my lungs and others in the subcutaneous area of my back. Dr. Kirkwood thought I was a one off. Based on my 25 yrs. in the Kodak research labs as an analytical chemist, I was able to research why my treatment worked.


I would like to present it to you so you can expand on the knowledge and put it to practice.


Please don’t let it fall on deaf ears. We the patients need your help to think outside the box and push the Melanoma research to new frontiers.



Melanoma and The Magic Bullet (Monoclonal Antibodies)





Take Care,

Jimmy B

Faltering Cancer Trials Melanoma.. Jim Breitfeller

Faltering Cancer Trials
Editorial
Published: April 24, 2010


The government’s system for judging the clinical effectiveness of cancer treatments, recently found to be in “a state of crisis,” must be repaired.

Here is a recent article from the New York Times. Thanks to Ed a carepage friend and colleage for bringing this to my attention.


Source:http://www.nytimes.com/2010/04/25/opinion/25sun1.html

Faltering Cancer Trials



We need the Patients to unite and get the best therapy for their condition. This is not rocket science, it is biochemistry at it's best. We need Big Pharma(Bristol Myer Sqiubb, Novartis,Pfizer, Plexikkon, Hoffman La Roche and others) to step up to the plate and do what is ethical. Not just looking at their bottom line. Without patients/consumers, these drug companies would not exist.

Our future survival is in our hands. The cure is out there. We need the medical community to take notice.




Take Care,
Jimmy B

Letter to Dr. Rosenberg on Combinatorial Therapy using Anti-CTLA-4 Blockade and High Dose Interleukin -2 3-19-2010 Melanoma..Jim Breitfeller

Dr. Rosenberg, during my search for answers about my therapy, I took notice of a combinatorial trial that you headed in 2003.

Study Start Date: February 2003

Detailed Description:

OBJECTIVES:

• Determine the maximum tolerated dose (MTD) of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4) in combination with high-dose interleukin-2 (IL-2) in patients with metastatic melanoma. (Phase I is closed to accrual as of 4/13/2004).

• Determine the activity of MDX-CTLA4 administered at the MTD with high-dose IL-2 in these patients.

• Determine whether the administration of IL-2 alters the pharmacokinetics of MDX-CTLA4 in these patients.

• Determine the safety and adverse event profile of this regimen in these patients.
OUTLINE: This is an open-label, dose-escalation study of anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody (MDX-CTLA4).

• Phase I: Patients receive MDX-CTLA4 IV on days 0, 21, and 42. Patients also receive high-dose interleukin-2 (IL-2) IV over 15 minutes every 8 hours for up to 15 doses beginning on days 22 and 43. Treatment repeats every 63 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with an ongoing partial response and no greater than grade 1 toxicity may receive additional courses of therapy. Patients who require discontinuation of MDX-CTLA4 due to toxicity may continue receiving IL-2 at the discretion of the investigator.

Cohorts of 3-6 patients receive escalating doses of MDX-CTLA4 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. (Phase I is closed to accrual as of 4/13/2004).

• Phase II: Patients receive treatment as in phase I at the MTD of MDX-CTLA4. Patients who achieve a partial or complete response and later develop recurrent or progressive disease may be retreated at the same dose.

Patients are followed at 3 weeks, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 3-51 patients (3-18 for phase I and 19-33 for phase II) will be accrued for this study within 1 year. (Phase I is closed to accrual as of 4/13/2004).

Based on knowledge gained over the last decade, I believe it warrants us/you to revisit this combinatorial approach.

Base on Dr. Wolchok’s research, the dose of the anti-CTLA-4 was to low to shift from tolerance to activation. Also, the addition of the HD IL-2 was added at the time to proliferate the CD4+ T-cells which may have caused a five fold expansion of the Tregs. There is now new data that suggests that IL-2 addition should be added after the contraction of the CD4+ T-cells. Et al Wherry.

By adding the The HD IL-2 after the expansion of the T-cells, IL-2 therapy was highly beneficial during the death phase, resulting in increased proliferation and survival of tumor-specific T cells. IL-2 treatment also increased proliferation of resting memory T cells.

If you add the combination of IL-2 and TGF- beta (tumor secreted) at the beginning of the treatment, it induces naive or total CD4+CD25– cells to develop strong suppressive effects both in vitro and in vivo according to Horwitz et al 2001. The T-Cell differentiation is pushed towards developing Treg suppressive immune cells.
So increasing the dose of Anti-CTLA-4 Blockade and delaying the addition of the HD IL-2 can have a dramatic effect on the overall response of the immune system. Here is a graphic representation of the protocol.







I know you will get a synergistic response with this protocol because it happen to Dr. Vivian Bucay and myself.







Please, if you get a chance, consider this new protocol and revisit the combinatorial
therapy of Anti-CTLA-4 Blockade and HD IL-2.

Thanks for you time

Best regards,

Jim Breitfeller

Melanoma and The Magic Bullet (Monoclonal Antibodies)


The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2


Eureka!!!!!! A possible cure for Melanoma, the Deadly Skin Cancer




Take Care,

Jimmy B