Breaking Tolerance to Invoke an Immune Response to Cancer (Melanoma)..Jim Breitfeller

This post has been in the works for five years. It is with my tenacity and help from researchers around the world I am able to present this paper. It is still in draft form but I thought was important enough to just get it out there. It may be to technical for the average person/patient but, it is well worth downloading and presenting to your oncologist and or medical team.

The gist of the paper is we have responders and non-responders to therapy. WHY?? with the help of Four on the most influential reseachers in the Melanoma field, Dr. Craig Slingluff, Dr. Thomas Gajewski, Dr.Kingston Mills, Dr. Jim Allison and others, I was able to put some puzzle pieces together to tell a story. A story that may just save your life

In short, the non-responders may be/are missing the "Danger Signals" inflammatory Cytokines. Why, because their tumors are most likely harboring M2 phenotype macrophages (TAMs) Tumor assisted Macrophages.

But these TAMs have plasticity. This means they can change phenotype based on their miroenviroment. With some coaxing they can be change into M1 macrophages which in turn activate the T-cells. This means the patient needs to have therapies that promote M1 and Th1 cells. Well both Dr. Allison and Dr. Mills have discovered ways to do just that.

Please take some time to download and read this historic paper. It just may be the game changer for cancer.

Breaking Tolerance to Invoke an Immune Response to Cancer (Melanoma



I am going end with four slides.










“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

Using Immunohistologic Characteristics of Tumor Infiltrating Immune Cells to the advantage of Melanoma Patients.Jim Breitfeller

In the research paper “Immunotype and Immunohistologic Characteristics of Tumor Infiltrating Immune Cells are Associated with Clinical Outcome in Metastatic Melanoma”1 et al Slingluff 2012, it breaks down the Immunohistologic Characteristics into three distinct immunotypes:

A) No infiltration of immune cells in the tumor’s microenvironment.
B) Infiltrating Immune cells only in close proximity to the tumor’s vascular system
C) Diffuse immune cell infiltrates throughout a metastatic tumor and its microenvironment.





Overall, the most predominant immune cells were T cells (53%), followed by the B cell lineage cells (33%), and then by macrophages (13%), with NK and mature dendritic cells only hardly present.

With the setting of the tumor’s microenvironment evaluated, we will focus the low survival immunotype A patients. How can we improve the overall survival and the immune response to Melanoma?

Here are just some of the therapies we have to date:

Dacarbazine (FDA approved)
High Dose Interluekin-2 (FDA approved)
Yervoy (Anti-CTLA-4) (FDA approved)
Zelboraf (Braf inhibitor) (FDA approved)

These therapies work well in a subset of melanoma patients but the overall survival rates are still quite low. We need to somehow combine these immunotherapies with a cancer vaccine to invoke an immune response with memories T-cells so we can eliminate any reoccurrence.
Oncologists have been working on this for decades.

I believe they may have discovered the right combination to just that. Dr. Kingston Mills and colleagues from the Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Immunotherapy with PI3K Inhibitor and Toll-Like Receptor
Agonist Induces IFN-g þIL-17þ Polyfunctional T Cells That
Mediate Rejection of Murine Tumors

Neil A. Marshall1, Karen C. Galvin1, Anna-Maria B. Corcoran1, Louis Boon3,
Rowan Higgs2, and Kingston H.G. Mills1,2

Authors' Affiliations: 1Immune Regulation Research Group, School of
Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity
College Dublin, Dublin, Ireland; 2Immunology Research Centre, Trinity
Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and
3Bioceros, Utrecht, The Netherlands


Dr. Mills and colleagues discovered that if you combine a PI3k inhibitor with TRL agonists (TRL-9 and or 5) with DC vaccine/tumor antigen, you invoke a tremendous immune response along with memory cells.





This combination actually tilts the T-cell differentiation towards the Th1 phenotype that is needed to activate the CD8+ T-cells. I believe this is a major breakthrough toward curing/stabilizing the Melanoma Cancer.

The immune activation by CpG ODN +(PI3k inhibitor) initiates with specific binding to the TLR-9 receptor in B cells and plasmacytoid DCs. TLR-9 ligation in DCs results in secondary activation of lymphocytes, macrophage, monocyte, NK-cell, and T-cell populations through the elaboration of cytokines generating a Th1 cytokine milieu. This results in increased NK activity as well as improved antigen presentation and T cell help that can augment
humoral and cell-mediated immune responses. In addition, TLR ligation results in the production of IL-6 by DCs, which helps overcome the suppressive effect of CD4 CD25 Treg cells.

We must break the tolerance to generate immune responses against the tumor antigens.

This combination developes a population of polyfunctional T-cells that produce interferon-gamma and IL-17, both potent mediators of the immune response. Moreover, the combination has a lasting effect. This combination also produces the “Danger Signal” that is needed to recruit the immune cells to the tumor’s microenvironment.






A fledgling startup company (Trimod Therapeutics) holds the patent to this technology.

Dr. Jeremy Skillington
http://www.trimodtherapeutics.com/

As stated in my previous post, we need a cancer vaccine with Anti-CTLA-4 and IL-2 to produce a lasting immune response. I believe this company holds the future of immunotherapy cure/stabilization for Melanoma and maybe more cancers. Only time will tell with the right Clinical protcol in place. This is years away, but holds a temendous promise due to the science behind it. We need to expidite this rationale for the good of the Cancer patients.





“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

'Holy Grail' cancer vaccine that blasts tumours in weeks hailed as huge leap in fighting disease..Melanoma ..Jim Breitfeller

'Holy Grail' cancer vaccine that blasts tumours in weeks hailed as huge leap in fighting disease

The vaccine contains DNA and fragments of tumor. These activate only the specific immune cells which target melanoma.

WHERE DID YOU HEAR ABOUT TUMORS SHEDDING ANTIGENIC PEPTIDES(ANTGENS)?

RIGHT HERE

Amy Dickenson had aggressive bone cancer but survived with the help of a cancer vaccine
The treatment, developed by the company Scancell, will initially be given both to patients with advanced skin cancer which has spread to other parts of the body, and to those in the earlier stage of the disease.
Trials will begin at hospitals in Manchester, Nottingham and Newcastle. If successful, the jab could be available within ten years.


Read more: http://www.dailymail.co.uk/health/article-1278836/Holy-Grail-cancer-vaccine-blasts-tumours-weeks-hailed-huge-leap-fighting-disease.html#ixzz0oJfHaJ6j

'Holy Grail' cancer vaccine that blasts tumours in weeks hailed as huge leap in fighting disease



Read more: http://www.dailymail.co.uk/health/article-1278836/Holy-Grail-cancer-vaccine-blasts-tumours-weeks-hailed-huge-leap-fighting-disease.html#ixzz0oJeWO9pT


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




"Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony."


~ Dr. Craig Slingluff ~


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

How therapy can teach your own immune system to fight cancer..Melanoma. Jim Breitfeller

How therapy can teach your own immune system to fight cancer

"The immune response to cancer
The immune system is our natural defense against disease. It destroys harmful bacteria and viruses that enter our bodies. In order to do this it has to recognize and label them as “foreign”. Once this happens, special types of cells in the immune system move in and destroy the invaders.

Our natural immune system can also detect cancer, because cancer cells are different from normal cells. In many cases, it will destroy these cancer cells before they turn into a detectable cancer.

Helping the immune system fight cancer
Sometimes our immune response to cancer fails and the cancer continues to grow. This can happen when cancer cells are not recognized by the immune system, or develop ways to cheat the system and escape detection. As a result, our immune system mistakes them for healthy cells and does not react.
Cancer immunotherapy aims to teach our natural defenses to identify cancer cells correctly – and then kill them.

ASCI*: a new approach that targets cancer antigens
ASCI* (Antigen-Specific Cancer Immunotherapeutics) is a new type of immunotherapy in development that targets cancer antigens and potentially destroys the cancer cells that bear these antigens. Cancer antigens are substances found on the surface of cancer cells, and are recognized as “foreign” by the body’s immune system.

ASCI* uses our own immune system to attack cancer. It does this by educating our immune system to identify and attack antigens displayed on cancer cells.
The immune system reacts towards the antigen in ASCI* – a reaction called immune response – and then attacks the cancer cells where this antigen is found."
Source:GlaxoSmithKline
http://www.immunotherapyforcancer.info/melanoma/index.shtml

There is only one major problem. Each melanoma patient has his or her own set of antigens based on their own tumors. Reseachers are trying to discover what are the major antigens that Melanoma patients exibit. For instance, MAGE-A3. There are literally thousands to choose from.

What if you get your body to produce them for you from your tumors. It sounds hard to believe but, radiation, chemotherapy with Dacarbazine plus (Patrin-2) Lomeguatrib and oblimersen sodium may help shed the right antigenic peptides. You have to get the right antigen to be presented on the dendritic cells acting as Antigen Presenting Cells (APCs) in order for the immune response to the cancer. The concentration of the antigen plays a major role in the intensity of the response.

Another problem is that you have to deplete or Block the suppressive function of the Tregs cells. This can be accomplished by lymphodepletion by preconditioning with cyclophosphamide and fludarabine or Anti-CTLA-4 blockade.

The final step of this process is the addition of interleukin-2 to activate and maintain the function of the CD8 + T-cells that mature into Cytotoxic T Lymphocytes (CTL’s). Dosing schedule and concentration of the drugs also play major role in weather an immune response is generated.



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




"Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony."


~ Dr. Craig Slingluff ~



Melanoma and the Magic Bullet (Monoclonal Antibodies)







Take Care,
Jimmy B

Combinatorial Therapy, Will the Big Pharmaceutical Companies do what Is Ethically Right?Melanoma..Jim Breitfeller

Combinatorial Therapy, Will the Big Pharmaceutical Companies do what Is Ethically Right?




They include Plexikkon,Bristol-Myer Squibb, Pfizer, La Roche and Novartis.


I and other researchers have come to the conclusion that Combinatorial Therapy may be the only way to beat The BEAST, Melanoma



“A very obvious combination that we are trying to move forward now is PLX4032 with ipilimumab. There is unanimity among the academic researchers that this must be investigated. Both companies see the logic, but are reluctant with neither of their drugs yet being FDA approved. As you know ipilimumab (and tremelimumab) have not overwhelmed the FDA yet as they were told to show a response rate greater than 10% and neither drug could do so. Most melanoma researchers believe that there are additional patients who get real and long-term benefit without having their tumors shrink significantly in size, but the randomized trials are needed to show that. The worrying sign is the outcome of the tremelimumab randomized trial. So, now we are down to waiting for the results of the dacarbazine vs. dacarbazine plus ipilimumab phase III trial. If this is negative, we are in trouble as ipilimumab will have no clear path forward with the FDA. If it’s positive, then the idea of moving ahead with combinations becomes much, much easier. But, even it that trial is negative, we know that CTLA-4 blockade can induce phenomenal responses in some. So, in that case, we have to figure out (1) who those patients are and, (2) how to make those responses happen in more patients. The other way of thinking of #2 is that PLX4032 doesn’t work for as long as we would like and that making those responses more durable would be desirable.”


~ Dr. Keith Flaherty ~


“ Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony.”


~ Dr. Craig Slingluff ~



Dr Markovic,. I thought you might be interested in this combinatorial therapy

“We actually just submitted a paper to this affect in a small clinical trial where we used a conventional chemotherapeutic agent to induce a systemic anti-tumor immune response by simply timing drug delivery. And, it worked! It was a small study, so the data is only descriptive. I'm gearing up to move to a large trial right now.”


~Dr. Svetomir Markovic~



“To answer your last question first: Mutations in B-Raf and N-Ras have been shown to cluster at specific nucleotides. This strongly suggests that there is a cellular mechanism which targets these sites in each gene. However, you are probably right, that anti-CTLA4 and IL2 are working by enhancing immune surveillance of your melanoma.”


~Dr. Natalie Ahn~



“In conclusion, the combination of MART-1/DC with concomitant tremelimumab is feasible in patients with metastatic melanoma, especially when tremelimumab is administered every 3 months, and results in durable objective clinical responses at the higher range of the expected objective tumor response rates with either therapy alone. Therefore, this combination warrants further study in patients with advanced malignant melanoma.”

~Dr. Antoni Ribas~


The rationale for the CTLA-4 and IL-2 combination is once you activated the CD4+ Tcell and it crossprime the CD8+ Tcell , the IL-2 needed for the maintenance and functionality of the CD8+ T-cell.
If lymphocytes are cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

“Fine theory but just theory that has never been tested in relevant clinical setting…”

~Dr. John M. Kirkwood~

"Glad to see your post on this series. From our perspective, the melanoma community isn’t waiting for a “miracle” to fall out of the sky to help patients. It’s clear that no single drug will likely effectively treat the disease; instead, a combination of drugs may be the answer. The Melanoma Research Foundation (MRF) is coordinating the Melanoma Breakthrough Consortium to accelerate research by bringing together leaders in drug development, laboratory and clinical research to find effective treatments. This collaboration will take years off the process. Patients with advanced melanoma have few or no treatment options and there’s no doubt in the urgency of moving forward to test new therapies today. More information is available at http://www.melanoma.org."

~Tim Turnham~
Executive Director
Melanoma Research Foundation




This is why we the patients need the Pharmaceutical companies to work together. Each therapy will not work alone as a single agent. The response rate is between 10 and 22 percent for each therapy. If you do a sequential treatment with the proper dosage and timing, you will see a synergistic outcome.

“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”


~Greg Simons~


If we are taking all the risk, shouldn’t we have a say in our Destiny?
“We need to all work together for the common good of the Melanoma Patients”
“We need to take greed out of the equation and just do what is ethically for humanity”

~Jimmy B~

Which elevator will you, The Pharmaceuticals Companies will Take?



Take Care,

Jimmy B

A Roller Coaster Chase for a Cure, Dr. Keith Flaherty Story..Melanoma..Jim Breitfeller

A Roller Coaster Chase for a Cure, Dr. Keith Flaherty Story

Published: February 21, 2010

PHILADELPHIA — His patient, a spunky Italian-American woman in her 60s, was waiting in an exam room down the hall for the answer: Was the experimental drug stopping her deadly skin cancer?


THE INVESTIGATOR Dr. Keith Flaherty oversees the testing of a drug known as PLX4032 calling it the best hope against melanoma “because it is based on what makes cancer tick.”


But as Dr. Keith Flaherty read out the measurements of her tumors from the latest CT scan, he could not keep the distress from his voice.

“She’s worse,” he said to the clinical trial nurse at the University of Pennsylvania’s melanoma clinic.

Source:http://www.nytimes.com/2010/02/22/health/research/22trial.html?pagewanted=1

A Roller Coaster Chase for a Cure, Dr. Keith Flaherty Story


As you can read, The research doesn't happen over night. You need a clinical Researcher that believes in the science.

I myself believe in our approach in how to get the host's immune system to see the Melanoma Cancer tumor cells. I have pages of Universities, Hospitals and Drugs companies following my blog at one time or another.

I even got this note from a world renowned Clinical Researher:

Dear Mr. Breitfeller,

Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony. I wish you success in your treatments and in your work to understand and to explain the immune response to cancer.

Craig Slingluff

Craig L. Slingluff, Jr. M.D.
Joseph Helms Farrow Professor of Surgery
Division of Surgical Oncology
Vice-Chair for Research
Director, Human Immune Therapy Center
University of Virginia

I have seen this treatment work. Until we have a Clinical trial in place, we won't know what the response rate would be.

We need more Clinical Researchers and Oncologists willing to step and think outside the box. Follow their passion and gut feelings to pursue a CURE. I tip my Hat to Dr. Keith Flaherty. Thanks for thinking outside the box!!!



Melanoma and The Magic Bullet (Monoclonal Antibodies)



Take care

Jimmy B

Melanoma_Missionary


"Today might be the worst day of your life...but tomorrow could be the best. You just have to get there."
~Unknown~

Identification and Validation of Combination Therapies for Melanomas..Jim Breitfeller

FW: Identification and Validation of Combination Therapies for Melanomas

I got my Christmas Wish!!!!!!!!!!!!!!!!!

-----Original Message-----

From: Slingluff, Craig *HS [mailto:CLS8H@hscmail.mcc.virginia.edu]

Sent: Thursday, December 24, 2009 11:51 AM

To: dbreitfe@rochester.rr.com

Cc: Weber, Michael J - Cancer Center *HS; Engelhard, Victor H

Subject: RE: Identification and Validation of Combination Therapies for Melanomas

Dear Mr. Breitfeller,

Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony. I wish you success in your treatments and in your work to understand and to explain the immune response to cancer.

Craig Slingluff

Craig L. Slingluff, Jr. M.D.

Joseph Helms Farrow Professor of Surgery

Division of Surgical Oncology

Vice-Chair for Research

Director, Human Immune Therapy Center

University of Virginia

Charlottesville, VA 22908

cls8h@virginia.edu

434-924-1730

http://www.box.net/shared/kjgr6dkztj
Melanoma and the Magic Bullet (monoclonal Antibodies)



Michael J. Weber, Ph.D.
Professor of Microbiology
Research Interests:
Signal Transducing Kinases in Cancer





Signal transduction by serine/threonine kinases
The Weber laboratory utilizes tools of cell biology, protein chemistry and molecular biology to understand how signal transduction pathways control cell growth and apoptosis and how these controls are altered in cancer. A major focus of this research is on the MAP Kinase cascade, a ubiquitous signaling pathway that generates specific biological outcomes dependent on biological context. Recent findings of the lab have demonstrated an important role for "scaffolding proteins" that assemble components of the signaling cascades. They recently discovered the MORG1 scaffold protein (MAP Kinase Organizer) that regulates responses to LPA but not EGF. Signaling scaffolds can control the location, regulation, timing, substrates, biological functions, and suitability for therapeutic intervention of a signaling pathway. This research made use of the Biostatistics Core, to help evaluate multi-factorial responses to mitogens, and the Mass Spec and DNA cores for molecular and proteomic analysis.

The lab pioneered the use of phosphorylation-site specific antibodies to probe archival paraffin-embedded pathology specimens, and discovered that the MAP Kinase cascade was activated in prostate cancer. Activation of this pathway is sufficient for and can be necessary for progression of prostate cancer to an androgen-independent disease. Therefore the Ras-MAP Kinase pathway is an attractive target for therapy of advanced prostate cancer.

Current research aims to determine how to select combinations of therapies in cancer treatment.


Merry Christmas

Jimmy Breitfeller






Take Care,

Jimmy B