Beating the Odds.. Did you Ever Wonder??Melanoma..Jim Breitfeller

Introduction:

"We are pleased to offer you in this website the following prediction tools for predicting the clinical outcome of an individual patient with localized or regional cutaneous melanoma. The prediction tools can be used to predict the 5 and 10-year survival rates from initial diagnosis (with a 95% confidence interval) for an individual patient based on his/her relevant clinical and pathologic information.

The predictive models were developed and validated using a combined database (n=28,047) from 11 major institutions and study groups participating in the development of the 7th edition of the American Joint Committee on Cancer (AJCC) Melanoma Staging System. This database includes 25,734 patients with localized melanoma and 2,313 patients with regional melanoma with relevant information available for model development. For detailed results regarding our prognostic factor analyses, model development and validation, please see the relevant manuscripts listed in the References section. Several additional useful prediction tools currently under development will be added to this website in the near future."

Source:The American Joint Committee on Cancer (AJCC) Melanoma Staging System

Survival Prediction Tool


Now that you have your prediction, it is time to be proactive in your therapy to predict them wrong.

1) Find the best Melanoma Care center that is closest to you
2) Evaluate the Melanoma Oncologist
3) You want cutting edge therapy
4) Get the mutation profile of your tumors
5) Make sure you gather a team of experts
6) Don't take the wait and see attitude
7) Be your own advocate

Here is my prediction based on my intial evaluation.

Estimated Survival Rates
(95% Confidence Interval)

1-Year 2-Year 5-Year 10-Year
87% 76% 53.3% 44.1%
(79.9% - 94.8%) (65.3% - 88.5%) (39.8% - 71.4%) (30.5% - 63.7%)



Keep the Faith!!!!

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

Eureka!!!The Right Immune Response..It is All in the Timing and IL-2 Concentration!!! Melanoma..Jim Breitfeller

So now we have the immune response in full progress. Are we creating the right response?

The difference between CD4+ T-cells and CD8+ T-cells revealed herein must be
interpreted in the context of its significance for the development of an effective
T cell immune response. Within T cell populations, CD4+ T-cells are the primary
source of IL-2 after antigen activation. Consequently, the finding that CD4+ T-cells
cell clonal expansion is only about 25% of the proliferative expansion achieved by
CD8+ T-cells indicates that IL-2 itself is the major parameter retarding clonal
expansion within the total cell population; especially because the rate of T-cell
proliferation is directly dependent on the amount of IL-2 available to the cells. et al Kendall A Smith

The ratio of CD4+ to CD8+ is about 2:1.
Thus, the immunologic relevance of the CD4+ T-cells IL-2 refractory state resides in
its potential as a feedback regulatory control retarding the extent and duration
of IL-2-dependent CD4+ T-cells and CD8+ T cell clonal expansion, ensuring that IL-2-
producing cells ultimately will become limiting.
This interpretation is entirely consistent with observations in lab experiments which indicate that IL-2 rapidly disappears from the culture medium of stimulated T cells.

So what happens if you have excess IL-2 in the Medium?
Studies show that a premature development of CD4+ T-cells IL-2-unresponsiveness arises and the CD4+ T-cells loose their functionality.
This means that premature excess of IL-2 can lead to unresponsiveness of the CD4+T-cells.

Thus, two mechanisms contribute to the depletion of IL-2 from the Medium of rapidly proliferating T cells:

1. The IL-2 internalization and degradation (the uptake) by responding cells
2. The end of CD4+ T-cells + (IL-2 producer) cell proliferative expansion


IL-2 concentration in the surrounding cell environment can regulate the expansion of the CD4+ T-cell population by effecting cell death.
As you keep the IL-2 concentration limiting, you can change the expansion profile if the CD4+T-cells. At low concentrations, the expansion distribution is sharpe and evenly distributive on the time axis. On the hand, at higher or excess concentrations, the distribution becomes skewed, with a longer life cycle.

If the addition of IL-2 is on or before the maximum propagation of the CD4+ T cells, the Tregs population can increase 5-fold in a 96 hour period based on certain growth mediums.
So by increasing the Treg population, you make it that much harder to break the immune tolerance to start an immune response.

So by limiting the excess IL-2 that is introduced into the host at the early expansion phase, you limit the expansion of the CD4+ T-cells. As the Tregs are a subset of the CD4+T-cells, you limit the expansion of the Tregs. By limiting the Tregs and CD4+ T-cells, you limit the CTLA-4 receptors. So blocking the B7 receptors with anti-CTLA-4 antibodies, and limiting the IL-2 in the matrix, you can shift the tolerance balance toward activation.


It is widely accepted that the CD4+ T-cells expand before the CD8+ T-cells.




Activation and Differentiation of (CTLs) Cytotoxic T Lymphocytes

Naïve CD8+ T-cells are referred to as CTL-precursors (CTL-Ps), which are incapable of performing any function other then recognizing the class I MHC-antigen complex on the Tumor cells through the (TCR) T Cell Receptor. For activation, the CTL-P needs at least three signals:

1. Antigen specific signal transmitted by the MHC I peptide/TCR complex for the recognition of the Antigen

2. The Costimulatory signals transmitted by the CD28 receptor and the B7 molecule of the Antigen Presenting Cells (APCs)

3. Cytokine induced signal, IL-2 interaction with the IL-2r (receptor) on the CTL-P leading to activation and differentiation of the CTL-P into effector CTL

The Cytokine IL-2 came from the TH1 cells which means the CTL-P is IL-2 limited and can only be activated by the secreted IL-2 if there is any to be had or by introducing IL-2 through IL-2 therapy. Now you know the reasoning behind using the IL-2 therapy as the second part of the combinatorial Therapy. If there is not enough IL-2 in the host environment, you will only get partial expansion of the CTLs. It may not be enough to eradicate large bulky tumors.

The Interluekin-2 plays another role in this Melanoma Maze. In a study by Janas et al, Il-2 increases the expressions of the perforin and granzyme A, B and C genes in the CD8+ T-cells. This increase expression causes the CD8+ T-cells to mature into Cytoxic T Lymphocytes (CTLs). The exogenous IL-2 is required for the granzyme proteins. CTLs have cytoplasmic granules that contain the proteins perforin and granzymes. A dozen or more perforin molecules insert themselves into the plasma membrane of target cells forming a pore that enables granzymes to enter the cell. Once in the tumor cell, these enzymes are able to breakup (lyse) the cell and destroy it. This is the beginning of the end for the cancer cells. The tumors begin to shrink and the rest is history.

Research suggests that the primary mode of the destruction of the tumors by CTL is by initiating death through the Fas-FasL pathway. Studies have shown that CTLs store Cytotoxic proteins in the form of granules in their cytoplasm. These proteins belong to two categories:
1. Perforins: involved in pore formation
2. Granzymes: responsible for hydrolysis of the cellular products.

Granzymes breaks down the tumors cells just like your detergent enzymes in your laundry detergent.

Immediately following a CTL contact with the tumor cell, the Golgi sacks load with granules and granzymes which create pores to allow the granzymes to enter and destroy the tumors cells.


So what if there is not enough IL-2 produced to supply the overall expansion?

We know the Naïve CD8+ T-cells needs IL-2 for the activation and the differentiation into effector T-cell call Cytotoxic T Lymphocytes (CTLs). We also know IL-2 is needed to upregulate perforin and granzyme A, B and C genes which need to turn the effector cell into a cytotoxic killing machine.

Does the timing of the addition of IL-2 make a difference in the outcome of the immune response?

It surely does. There are a number of research papers that state if the IL-2 is added to early in the expansion phase, you produce non-responsive T-cells. As a matter of fact you could expand the subtype Tregs by a factor 5 under certain conditions. On the other hand, waiting until the expansion is at just passed peak or contracting generates the Cytotoxic T Lymphocytes (CTLs) that we as patients, have been waiting for. That is why Dr. Rosenberg uses IL-2 in his ACT Therapy. It is to generate and maintain the Cytotoxic T Lymphocytes.









Eureka!!!The Right Immune Response..It is All in the Timing and IL-2 Concentration!!! Tumor Shrinkage!!!!
Complete Response!!!!!!


“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 "Danger Signal" To start the Immune Response...Th17 Cells secreting IL-17..Melanoma 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

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

The missing third signal "The Danger Signal"Melanoma..Jim Breitfeller

Th17 Cells Secrete IL-17 in the Tumor Microenvironment causing inflammatory symptoms "The Danger Signal"improves Survival in a Murine Model of Pancreatic Cancer and in Melanoma also.

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

"Th17 cells and IL-17 participate in antitumor immunity by facilitating T cell recruitment to the tumor site and CD8+ T cell priming and effector differentiation suggests a new avenue for developing Th17 cell-based therapy."

~S. A. Rosenberg~


"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



Thus, the addition of IL-6 and IL-1β to the tumor microenvironment skews the balance toward Th17 cells in a murine model of pancreatic cancer and Melanoma.

So we need to suppress the Tregs and generate Th17 T-cells to initiate the right immune response.




“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 Drugs Stir Debate on Rules of Clinical Trials..Melanoma - Jim Breitfeller

New Drugs Stir Debate on Rules of Clinical Trials..Melanoma -

New Drugs Stir Debate on Rules of Clinical Trials..Melanoma PLX4032


We should let the FDA ,Congress and Plexikkon know how us, the Patients feel about the clinical trial protocol process.
It doesn't smell right.


Stop monkeying round with Our Life. We are just trying to survive.



Peter Hirth CEO Plexxikon


Try These. I am not sure of the CEO’s email. Just try and see if they bounce back.

kphirth@plexxikon.com CEO

phirth@plexxikon.com CEO


kglaub@plexxikon.com President








Richard Pazdur
Richard Padzur to run its new Office of Oncology Drug Products (OODP)
pazdurr@cder.fda.gov

Plexikkon should open a compassionate care use to the patients that have no other trial available.Peter Hirth, show some compassion to your customers/patients.

Please Make the right choice!!!






Please write about your disgust to the above email addresses

Thanks in advance



“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"Melanoma..Jim Breitfeller

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.

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 approximatly 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 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 and invoke a robust immune response to the Melanoma Cancer.

“Our data altogether suggest the following model: Th17 cells go to the tumor site and, by secreting IL-17, activates residential cells to produce CCL2 and CCL20, which provokes the mobilization of DCs and other leukocytes to the tumor site. DCs uptake tumor antigens in the lung or tumor site and migrate to the lymph nodes where they activate CD8+ T cells against the tumor. The new wave of effector CD8+ T cells migrates back to the lung or tumor site and kills established tumors.

Therefore, our data demonstrating that Th17 cells and IL17 participate in antitumor immunity by facilitating T cell recruitment to the tumor site and CD8+ T cell priming and effector differentiation suggests a new avenue for developing Th17 cell-based therapy for tumors or chronic viral infections and as an adjuvant for vaccinations.”

(Dudley and Rosenberg, 2007; Rosenberg and Dudley, 2004)

Conclusion: We not only want to supress the Tregs, we also need to produce the "Danger Signal" to optimally activate TH1 differentiation and lead to clonal expansion of T cells to generate a robust tumor-specific immune response.






The Missing Link in T-cell activation using a Vaccine, "The Danger Signal"


“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

Poised for progress..Melanoma ..Jim Breitfeller

Poised for progress
By Bill Schaller

Dana-Farber Cancer Institute

Friday, September 17, 2010

A new focus on the immune system’s ability to both unleash and restrain its attack on disease has led scientists at Harvard-affiliated Dana-Farber Cancer Institute to identify cells in mice that prevent the immune system from attacking the animals’ own cells, protecting them from autoimmune diseases such as multiple sclerosis, Type 1 diabetes, and lupus.

The discovery, recently reported by the journal Nature, may give scientists an effective way of operating the immune system’s internal “control panel,” leading to improved therapies for a variety of diseases — from vaccines that prompt the immune system to stage a sustained assault on cancers, to treatments that derail the biological onslaught associated with autoimmune diseases. The fact that human immune system cells share key features with those in mice makes the prospect of such advances quite realistic, the study authors say.

“The traditional view of the immune system is of specialized groups of cells poised to attack foreign pathogens [disease-causing agents],” said senior author Harvey Cantor, the Baruj Benacerraf Professor of Pathology at Harvard Medical School and chair of the Department of Cancer Immunology and AIDS at Dana-Farber. “While that model is generally correct, we’ve come to appreciate that the immune system, like other complex biological information systems, includes a counterbalance mechanism — a set of cells programmed to suppress the immune response. Such cells are essential to preventing excessive reactions to pathogens and misguided attacks on the body’s own cells.”

The search for cells involved in quieting the immune response has previously focused on immune system cells known as CD4+ T cells, some of which have been shown to prevent abnormal inflammation in response to disease or infection. In the new study, lead author Hye-Jung Kim and her colleagues found that CD8+ T cells (known as killer T cells because of their ability to kill diseased cells) also include a subset that helps dampen the immune response. Instead of reducing inflammation like their CD4 cousins, the CD8+ T regulatory (CD8+Treg) cells ensure that the immune system doesn’t produce antibodies that attack normal cells.

The Dana-Farber team discovered how CD8+ Treg cells accomplish this feat. They mingle with cells known as follicular T-helper cells, which are intermediaries that prompt the immune system’s B cells to make disease-fighting antibodies. The meeting with CD8+ Treg cells essentially shuts off the follicular T-helper cells, preventing them from interacting with B cells. No interaction means no production of antibodies, which means no assault on an animal’s normal, healthy cells.

The critical point of contact between CD8+ Treg cells and follicular T-helper cells is a protein on the helper cells called Qa-1. When Kim and her colleagues bred a strain of mouse with abnormal Qa-1, the animals developed a form of lupus. The reason: the CD8+ Treg cells couldn’t latch onto the defective protein, leaving the follicular cells free to order the B cells to produce antibodies, some of which targeted the animals’ own tissue.

The significance of this work is that CD8+ Treg cells represent a new lever for raising or lowering the strength of the immune response. This class of cells, it turns out, depends for its survival on a cytokine (a regulatory compound) called interleukin 15. Increase the supply of CD8+ Treg cells and the immune response is suppressed — a potentially powerful way of dealing with autoimmune diseases. Decrease the amount of such cells and the immune response can be invigorated and extended — a useful complement to vaccines that unleash the immune system on cancer.

“Experience has shown that vaccines that simply activate or expand the number of T and B cells are not likely to result in a prolonged, robust anti-tumor response,” Cantor explains. “The balancing mechanism within the immune system means that when more disease-fighting cells are generated, there’s a countervailing increase in the number of immune-suppressing cells that are generated. The key is to break that loop. This work brings that goal closer.”

Source:http://news.harvard.edu/gazette/story/2010/09/poised-for-progress/

A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer
It is recruiting.

A Phase I Study of Intravenous Recombinant Human IL-15 in Adults With Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer

Maybe a combination of Anti-CTLA-4 blockage + IL-15 may be another protocol that will erradicate the Melanoma Tumor



“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