Combinatorial Therapy Will Revolutionize Cancer Therapy ...Just wait until ASCO 2015!!

Bristol-Myer Squibb Pharmaceutical Research Institute
Attention: Elliott Sigal
Route 206, Provinceline Road
P.O. Box 4000
Princeton, New Jersey 08543 U.S.A...

 Date: 3-10-2010

Dear Dr. Sigal:
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.

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.

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.

“Our Life depends on it.”

Thanks again.
Sincerely,
Jim Breitfeller

 

 

“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 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

A very Happy Father's Day from a stage IV Melanoma Survivor..Jim Breitfeller

I want to thank all the people that has made this day a very special Day.


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".

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 "Yellow Brick Road". I have won the "lottery of life."

Many Thanks

“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
 

Living Medical Textbook: Update to the Tumor Immunology and Immunotherapy: Metastatic Melanoma ..Jim Breitfeller

Living Medical Textbook: Update to the Tumor Immunology and Immunotherapy: Metastatic Melanoma Edition With Dr. Jeffery Weber and Dr. Bernard Fox

Jeffrey S. Weber, MD, PhD
Senior Member, Moffitt Cancer Center
Director, Comprehensive Melanoma Research Center
Professor, Department of Oncologic Sciences
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida


Bernard A. Fox, PhD
Chief
Laboratory of Molecular and Tumor Immunology
Providence Portland Medical Center
Earle A. Chiles Research Institute
Portland, Oregon


This "living" textbook is an interactive and up-to-date resource to support learning in the field of tumor immunology, and more specifically focuses on melanoma treatment and management. Throughout each chapter you will find supplemental hyperlinks to external multimedia resources—including illustrations, ...more



Source:http://www.livingmedicaltextbook.org/Activity/index.cfm?jn=2001&sj=2001.01&i=5

You must turn off my playlist by clicking on the radio button on my playlist located on the right column almost all the way down the scrollbar

Listen as Dr. Weber interviews Dr. Fox about the ability of helper T cells, cytolytic T cells, and natural killer T cells to mediate tumor regression.


Listen as Dr. Weber interviews Dr. Fox about the ability of regulatory T cells to dampen the immune response to tumor cells.



Listen as Dr. Weber and Dr. Fox discuss investigational immunotherapies that improve T cell targeting of tumors.


Special Feature: Replay the complete audio interview between Dr. Weber and Dr. Fox




“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

Reopening the compassionate Drug Use (ipilimumab) Letter to Bristol-Myer Squibb 3-10-2010

Bristol-Myer Squibb Pharmaceutical Research Institute
Attention: Elliott Sigal
Route 206, Provinceline Road
P.O. Box 4000
Princeton New Jersey 08543 U.S.A


Dear Dr. Sigal:

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 have been restored.

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.

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.

“Our Life depends on it.”




Thanks again.
Sincerely,
Jim Breitfeller

--------------------------------------------------------

-----Original Message-----
From: Sigal, Elliott [mailto:]
Sent: Saturday, February 27, 2010 5:03 PM
To: 'dbreitfe@rochester.rr.com'
Cc: Humphrey, Rachel; Furey, Tracy
Subject: Re: The Perfect Storm..Therapeutic use of Anti-CTLA-4 Blockage and IL-2 to enhance T-cell responses in vivo





Jim,

We are very interested in combination trials. One is ongoing with a PD-1 antibody and many more are planned especially with a variety of targeted therapies. I can assure you we have prioritized the ipilimumab program as high as any in the company. Our compassionate use program will reopen hopefully in late March. Thank you for your continued interest. Your ideas have been widely circulated.

Elliott


http://www.box.net/shared/kjgr6dkztj

Melanoma and The Magic Bullet (Monoclonal Antibodies)




Take Care,

Jimmy B

Am I seeing Double?? Melanoma..Jim Breitfeller

I was able to get in touch Dr.Bucay the Dermatologist that went through therapy. She gave me her timeslines so I graphed it.



I guess the main take away is "There is Hope". Two complete responses doesn't make a cure. We used two different monoclonal antibodies with two different regimens - (medicine) a systematic plan for therapy (often including diet). It is interesting to note that the time between therapies are very close.

The overall time difference my be due to the fact that we had different tumor loads.

My bet is on the timing!!!


Take Care,

Jimmy B

Surviving Advanced Melanoma..A DERMATOLOGIST'S PERSONAL PERSPECTIVE.Melanoma.Jim Breitfeller

A DERMATOLOGIST'S PERSONAL PERSPECTIVE
Vivian W. Bucay, MD
Clinical Assistant Professor
Dept of Physician Assistant Studies
University of Texas Health Science Center - San Antonio, TX


"As a dermatologist in clinical practice since 1991, I have had many opportunities to make a positive impact on patients' lives by being the first to diagnose and treat skin cancers, above all nonmelanoma skin cancers. Fortunately, almost every patient has had a good outcome, primarily because of early diagnosis and intervention. Like most dermatologists, I understand that if I encounter high-risk melanoma or advanced disease, clinical management will most often become the responsibility of surgical and medical oncologists, while I will navigate shallower waters, such as screening family members and reviewing pertinent but often confusing literature to assist the patient and family in making important decisions regarding treatment.

I have gained quite a new perspective on melanoma, however, since becoming an advanced melanoma patient myself in 2006. I have previously chronicled my personal battle with the disease twice before, first in San Antonio Medicine, a publication of the Bexar County Medical Society, in an issue dedicated to the physician as patient,1 and second, in the 2008 Skin Cancer Foundation Journal, a publication targeted to the lay public.2

My purpose in this issue of The Melanoma Letter is twofold: to present treatment options for Stage III and Stage IV melanoma in the manner in which they became relevant for me, and to emphasize that good outcomes are not only possible, but becoming more attainable every day despite seemingly unfavorable odds.

DIAGNOSIS
On May 5, 2006, I asked my physician assistant (PA) to look inside my umbilicus to see whether or not she noticed anything unusual; I had noticed a white "residue" that appeared on dark clothing. There was no itching, bleeding, or tenderness, just a whitish discharge that had appeared intermittently for the previous few weeks. I had no recollection of any existing abnormality in the region, keeping in mind that I had seen my umbilicus at its peak convexity during each of my three pregnancies. Nonetheless, as I mentally reviewed the differential diagnosis — psoriasis, eczema, seborrheic dermatitis — melanoma was not on the list while I was undergoing a routine shave biopsy; my PA chose to do the biopsy for safety's sake despite noting nothing unusual herself.

So we were both surprised when we received the diagnosis by phone on May 10 from the dermatopathologist to whom I routinely send my patients' biopsies: amelanotic malignant melanoma, possibly metastatic. I suspected (or hoped) that it was a false positive produced by using a shave specimen rather than a full excisional biopsy. However, there was no error in the diagnosis, as immunohistochemistry proved positive for S-100, HMB-45, and MART-1."

The rest can be found at Surviving Advanced Melanoma..A DERMATOLOGIST'S PERSONAL PERSPECTIVE



I am amazed how similar my treatment and Dr. Bucay's was, and how we had the same outcome NED. This reinforces my scientific theory on the combination of the two treatments.

I am in the process of trying to get in touch So we can compare time lines.



Take Care,

Jimmy B

Watch Dr Jeff Weber, Moffitt Cancer Center, Tampa, Florida, USA, ANTI-CTLA-4: A new immunological approach on ecancer tv. Cancer journal: online cancer news, clinical oncology research, cancer information and latest cancer studies - open access cancer journal: ecancermedicalscience | ecancermedicalscience

Watch Dr Jeff Weber, Moffitt Cancer Center, Tampa, Florida, USA, ANTI-CTLA-4: A new immunological approach on ecancer tv. Cancer journal: online cancer news, clinical oncology research, cancer information and latest cancer studies - open access cancer journal: ecancermedicalscience ecancermedicalscience

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Characteristics of the Innate Immune ResponseMelanoma ..Jim Breitfeller

The immune system protects against pathogens that penetrate the physical barriers of the skin and mucous membranes lining the digestive, respiratory, and reproductive tracts. It is subdivided into the innate and the adaptive immune systems. These two systems work differently, but collaboratively, to provide a powerful defense against microbial invaders. Increasing evidence suggests that the immune system also plays a role in detecting and eliminating tumor cells, and can be manipulated therapeutically against cancer.

Innate Immunity

Characteristics of the Innate Immune Response

The innate immune system provides a rapid but nonspecific response to the most common foreign pathogens.1 This system, in some form, is present in all animals, and some elements of it have existed for more than 500 to 700 million years.2 Cells of the innate immune system have specialized receptors (eg, Toll-like receptors) that recognize molecular structures or patterns that are characteristic of—and often indispensable parts of—common pathogens.3 As such, they recognize these pathogens immediately, even without having encountered them previously, and can react promptly. Disadvantages of the innate immune system are that it can recognize only a limited number of molecules, has limited ability to recognize viruses once they have entered normal cells, and has no "memory" and therefore cannot provide lasting protective immunity against these molecules.
The innate immune system is often sufficient to protect against the small quantities of common pathogens humans come into contact with on a day-to-day basis.2 When additional "help" is needed, the innate immune system activates and modulates the adaptive immune system.2,3
Cells of the Innate Immune Response

Macrophages.
Macrophages are the "sentinels" of the immune system. Present in large quantities under the skin, in the lungs, and in the tissues surrounding the intestines, these cells are in key positions to detect microbes where they first enter the body.2 The name macrophage means "large eater," and its primary responsibility is to rid the body of debris as well as pathogens, largely but not exclusively via phagocytosis.2,3

In their usual resting state, macrophages sample their environment and serve as "housekeepers," scavenging dead cells, cellular debris, oxidized lipoproteins, and other normal cellular by-products.2,3 When exposed to certain cytokines (eg, interferon gamma) released by other immune cells, such as helper T-cells and natural killer cells, macrophages become primed or activated. The activated macrophage engulfs a pathogen, containing it in a phagosome, which then fuses with a lysosome full of antimicrobial enzymes that destroy the pathogen. After digesting the pathogen, macrophages release various chemicals that increase the flow of blood to the area, trigger capillaries to allow extravasation of blood cells into the affected tissue, stimulate pain signals from nerves in the area, and release cytokines that facilitate communication with other cells in the immune system. As will be described in more detail later, activation also causes the macrophage to upregulate major histocompatibility complex (MHC) class II receptors on its cell surface, and protein fragments from the invading pathogen are transported to the MHC receptors and presented there for detection by helper T-cells and natural killer cells.2

Macrophages also have cell surface receptors (eg, the Toll-like receptors mentioned above) that enable them to detect molecules (eg, lipopolysaccharide, mannose) that are not normally found on human cells but are common cell wall components in typical pathogens.2 When a macrophage detects such molecules, it becomes "hyperactivated." The macrophage stops proliferating and becomes a virtual killing machine, growing larger and increasing the number of lysosomes and its rate of phagocytosis. It also actively migrates toward a foreign invader, even extending out "feet" to grab it up.2 In this state, macrophages also secrete tumor necrosis factor (TNF) alpha, interleukin (IL) 1, IL-6, and IL-8. These inflammatory cytokines help kill tumor cells and virus-infected cells and activate and summon other cells in the immune system.2,3

Neutrophils.
Neutrophils are highly phagocytic cells. Produced from myeloid precursors and with a lifespan of only 2 to 5 days, these cells circulate through the bloodstream, where they are within easy reach of all cells in the body until they are summoned.2,3

Cytokines and chemokines released by macrophages and mast cells draw neutrophils to the area of infection.2,3 It takes only about 30 minutes for neutrophils to exit the bloodstream and arrive fully activated at the site of an infection.2 Once there, they not only perform phagocytosis, they secrete cytokines (eg, TNF) to summon other immune cells and release various antimicrobial products from granules into the extracellular space.1-3

Mast cells and eosinophils.

These cells lie beneath exposed surfaces of the body (ie, the skin and mucosal barriers) and can survive for years. Their best-known function is to provide a defense against parasites. Mast cells are phagocytic and also contain granules of chemicals, most notably histamine. Eosinophils are poor phagocytes but do carry granules. When a mast cell or eosinophil detects a parasite, it "degranulates," that is, it unloads the chemicals.

Contributing Writer: Lauren Cerruto
Contributing Editor: Bernard A. Fox, PhD
Editor-in-Chief: Jeffrey S. Weber, MD, PhD





Take Care,

Jimmy B

The Role of the CTLA-4/PD-1 Pathway in Regulating T-Cell Response..Melanoma ..Jim Breitfeller

The Role of the CTLA-4/PD-1 Pathway in Regulating T-Cell Response

Jeffrey Weber, MD, PhD

The Role of the CTLA-4/PD-1 Pathway in Regulating T-Cell Response Flash Presentation

For those looking of information

Jimmy B

Novel Approaches to Metastatic Melanoma: Understanding the Potential of Immunotherapy.. Melanoma..Jim Breitfeller

Novel Approaches to Metastatic Melanoma: Understanding the Potential of Immunotherapy (Slides With Video)

Walter J Urba, MD, PhD ; Evan M Hersh, MD ; Jeffrey S Weber, MD, PhDPublished: 06/30/2008

This link was sent to me from a dear friend across the country.I would like to thank her for being an advocate.

It is a 20 min. video. You will now see and hear first hand why I am pushing so hard to be heard.

Source:http://cme.medscape.com/viewarticle/576528

Novel Approaches to Metastatic Melanoma


I have been in touch with Dr. Weber.

Take care

Jimmy B

Cutting Edge Technology “Infection-mimicking materials to program dendritic cells in situ”Melanoma .. Jim Breitfeller

Cutting Edge Technology “Infection-mimicking materials to program dendritic cells in situ”

Thanks to Donald Bohlken for bring this to my attention.

“I thought you might be interested in that attached article from the January 25, 2009 issue of the journal "Nature Materials" concerning a Harvard study of a new vaccine methodology which resulted in a 90% survival of mice infected with a melanoma strain which would normally kill them in 25 days. The article speaks of this result as a "cure".

The article synopsis notes: "Cancer vaccines typically depend on cumbersome and expensive manipulation of cells in the laboratory, and subsequent cell transplantation leads to poor lymph-node homing and limited efficacy. We propose that materials mimicking key aspects of bacterial infection may instead be used to directly control immune-cell trafficking and activation in the body. It is demonstrated that polymers can be designed to first release a cytokine to recruit and house host dendritic cells, and subsequently present cancer antigens and danger signals to activate the resident dendritic cells and markedly enhance their homing to lymph nodes. Specific and protective anti-tumour immunity was generated with these materials, as 90% survival was achieved in animals that otherwise die from cancer within 25 days. These materials show promise as cancer vaccines, and more broadly suggest that polymers may be designed to program and control the trafficking of a variety of cell types in the body."
This is Nano and Transdermal Technology at its best.

Implants Mimic Infection To Rally Immune System Against TumorsMain Category:

Melanoma / Skin CancerAlso Included In: Immune System / Vaccines; Medical Devices / Diagnostics; Biology / Biochemistry

Article Date: 25 Jan 2009 - 0:00 PST

“Bioengineers at Harvard University have shown that small plastic disks impregnated with tumor-specific antigens and implanted under the skin can reprogram the mammalian immune system to attack tumors.

The research -- which ridded 90 percent of mice of an aggressive form of melanoma that would usually kill the rodents within 25 days -- represents the most effective demonstration to date of a cancer vaccine.

Harvard's David J. Mooney and colleagues describe the research in the current issue of the journal Nature Materials.

"Our immune systems work by recognizing and attacking foreign invaders, allowing most cancer cells -- which originate inside the body -- to escape detection," says Mooney, Gordon McKay Professor of Bioengineering in Harvard's School of Engineering and Applied Sciences. "This technique, which redirects the immune system from inside the body, appears to be easier and more effective than other approaches to cancer vaccination."

Most previous work on cancer vaccines has focused on removing immune cells from the body and reprogramming them to attack malignant tissues. The altered cells are then reinjected back into the body. While Mooney says ample theoretical work suggests this approach should work, in experiments more than 90 percent of the reinjected cells have died before having any effect.
The implants developed by Mooney and colleagues are slender disks measuring 8.5 millimeters across. Made of an FDA-approved biodegradable polymer, they can be inserted subcutaneously, much like the implantable contraceptives that can be placed in a woman's arm.
The disks are 90 percent air, making them highly permeable to immune cells. They release cytokines, powerful attractants of immune-system messengers called dendritic cells.
These cells enter an implant's pores, where they are exposed to antigens specific to the type of tumor being targeted. The dendritic cells then report to nearby lymph nodes, where they activate the immune system's T cells to hunt down and kill tumor cells throughout the body.”

Source: Http://www.medicalnewstoday.com/articles/136473.php

Implants Mimic Infection To Rally Immune System Against Tumors



Donald Bohlken actually contacted one of the collaborators, Dr. Glenn Dranoff of the Dana Farber Cancer Institute and Harvard Medical School. He indicated: "We are initiating efforts to bring this to clinical testing, but it will take some time to adapt the procedures to patients. A one year time frame is a reasonable guess."

If this crosses over from the mouse model to the human model, we may have a winner on our hands. A 90 % response and if they are complete responses, this technology would surpass any therapy out there to date. The main take away is that they are prompting our immune system to recognize the tumors by activation of the T-cell. Rosenberg and Hwu and other colleagues are doing just that with (ACT) Adoptive Cell Transfer. Kirkwood, Camacho, Webber, Hodi, Maker, O’Day and Wolchok did that with anti-CTLA-4 blockage.

I can see the Light at the end of the tunnel!!!!!!!!!!!!!!!!!!!!!!!!!!!

Thank you Don for advocating for us and your Brother Ron who is a fighting Warrior of Melanoma.

I will post the research paper on Melanoma Missionary for everybody.

Jimmy B

I believe I am Half way There!!!!!!!! Melanoma Jim Breitfeller

I believe I am Half way there with the article "Melanoma and the Magic Bullet (Monoclonal Antibodies)". I have been doing the final research and ask Dr. Weber if my theroy is too much hand waving or not. You are going to ask, who the hell is Dr. Weber. I am glad you asked.

"Dr. Weber is the director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center, with the charge of bringing together basic scientists, clinical and translational investigators and prevention/epidemiology scientists in an integrated overall melanoma research effort that rapidly brings new drugs and ideas to the clinic. He works extensively with Drs. Vernon Sondak, James Mulé, Esteban Celis and Dmitri Gabrilovich, as well as others, to achieve these aims. Weber has an extensive history of conducting translational and investigator-initiated clinical trials. Dr. Weber is also a professor of Oncology and Medicine in the department of Interdisciplinary Oncology.
Dr. Weber received his doctorate in Molecular Cell Biology in 1979 from Rockefeller University. He received his medical degree from New York University Medical Center in 1980. He then completed an Internship and Residency in Medicine at the University of California. Dr. Weber also trained at the National Cancer Institute (1986-1990).
Dr. Weber’s clinical interests are in the immunotherapy of melanoma and other malignancies, with a focus on vaccines, adoptive immunotherapy, dendritic cell therapy and the use of immune modulating antibodies.
Dr. Weber’s research interests lie in the monitoring and characterization of T cell responses to vaccination in cancer patients, and in the establishment of in vitro models to facilitate the understanding of how immune modulating antibodies amplify T cell responses in patients. He is also interested in the mechanisms by which achieving autoimmunity induces regression of cancer

http://www.moffitt.org/Site.aspx?spid=F0B14BB585AB4205A5798A3E718234A0



Source:Dr. Weber



See, I want the information that I am going to provide is sound and realistic. I don't want to promise something that I can't deliver. I need to all my facts straight before releasing this information.

And that is why it is taking so long. I've been reseaching this for a long time and I want to present it right.

Take care

Jimmy B

Targeting Immune Stimulation: Clinical Application of Immunology Melanoma ..Jim Breitfeller

Contributing Writers: F. Stephen Hodi, MD and Lauren Cerruto
Contributing Editor: F. Stephen Hodi, MD
Editor-in-Chief: Jeffrey S. Weber, MD, PhD


Efforts to develop immunotherapies for cancer have historically involved vaccines and individual cytokines, which have produced benefits to only a small percentage of patients.

Recently, improved understanding of immune processes, such as the role of T-cell costimulatory molecules and regulatory molecules, has led to renewed efforts to develop immunotherapies to treat cancer. Current clinical trials are utilizing monoclonal antibodies (mAbs) to modulate costimulatory effects in the treatment of a variety of cancers. For example, two fully humanized mAbs that block cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) have advanced to phase III clinical studies in metastatic melanoma. Antitumor activity has been observed in melanoma and other malignancies after treatment with anti-CTLA-4 antibodies, as well as the potential for autoimmune-related toxicities.

Rationale for Targeting CTLA-4 in Patients with Cancer

http://www.livingmedicaltextbook.org/Activity/index.cfm?showfile=b&jn=1843&sj=1843.04

Living Medical Textbook Targeting Immune Stimulation: Clinical Application of Immunology





Jimmy B