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

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

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

Tremelimumab Shows Low But Durable Response Rate in Advanced Melanoma..Jim Breitfeller

Tremelimumab shows low but durable response rate in advanced melanoma
FEBRUARY 18, 2010

"NEW YORK (Reuters Health) - In a phase II trial in patients with advanced refractory or relapsed melanoma, tremelimumab (CP-675,206) showed a 6.6% objective response rate, with these responses lasting more than six months, a multinational group of researchers report in the February 1 issue of Clinical Cancer Research."

Source:http://www.curetoday.com/index.cfm/fuseaction/news.showNewsArticle/id/13/news_id/2350

Tremelimumab shows low but durable response rate in advanced melanoma


As you can see, the response rate is low as a monothrapy, but if you can get the tumors to shed antigentic proteins by combining with chemotherapy, irradiation and other molecules to stop the repair of the tumor Cell DNA, then you have antigens to present on the the (APCs) Antigen Presenting Cells. Interluekin-2 can be added at the end of the T-cell expansion to help grow and maintain the (CTLs) Cytotoxic T Lymphocytes.





adapted from Henry Stewart Talks by Jim Allison



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~

"Extraordinary Measures" Melanoma..Jim Breitfeller

"Extraordinary Measures"
Isn't this what we are trying to do?

Save our lives, save our love ones,

We have a theory, we need a clinical Trial to prove the theory.

Melanoma and the Magic Bullet (Monoclonal Antibodies)


Melanoma and the Magic Bullet (Monoclonal Antibodies)


We are Taking "Extraordinary Measures"

"Extraordinary Measures"




Take Care,

Jimmy B

Search for a Cancer Vaccine Beginning to Show Promise..Melanoma ..Jim Breitfeller

Search for a Cancer Vaccine Beginning to Show Promise

As Reported by TIME. 2009 Sept 14

The search for an effective cancer vaccine has been elusive until now, but positive results for separate vaccines against melanoma and lymphoma were finally reported this past June. Although the theory behind a cancer vaccine seems logical—enlist the immune system to seek and destroy cancer cells—it also contains an inherent problem, specifically, that cancer cells aren’t foreign pathogens, such as bacteria or viruses, but cells from a person’s own body. Getting a vaccine to work against cancer requires a deep understanding of how the immune system works and how malignant cells evade detection. A feature article in the September 14 issue of TIME, written by Alice Park, explains the quest thus far for cancer vaccines.

Defining a cancer vaccine

The Food and Drug Administration has approved vaccines against cervical cancer and liver cancer, but both of these diseases are caused by a virus (human papillomavirus and hepatitis B virus, respectively). Thus, the vaccines are actually targeting the virus. Nonviral cancers attributed to genetic mutations, environmental exposures, and other factors would require a vaccine that can accomplish primary prevention or prevention of recurrence. Such vaccines would need to prime the immune system to find every last cancer cell.

Cancer vaccines that didn’t work, but might

A vaccine for melanoma seemed on the horizon when researchers used extracts of melanoma tumors in developing Canvaxin. More than 1500 patients received the vaccine following treatment with surgery and chemotherapy, but the study was terminated after interim analysis showed that survival was no better for the vaccinated patients than for the nonvaccinated patients. Addition of interleukin-2, however, improved the rate of tumor shrinkage. Researchers working on a vaccine for follicular lymphoma took the combination approach one step further, by adding GM-CSF to a vaccine developed from each patient’s cancer cells. This combination extended disease-free survival by 47% over that achieved by patients who received a nonindividualized vaccine. Experience with this vaccine also indicated that the best time to administer the vaccine was when patients were in remission.

Creating a “foreign” tumor

Various strategies to manipulate a tumor to cause it to become more “foreign” are being investigated. One technique is to make the tumor look like a virus to the immune system. Another is to inhibit immune suppressors that tumors secrete. Along the lines of the bone marrow transplantation approach, some studies have used in vitro techniques to develop immune system cells, taken from the cancer patient, that will target those specific cancer cells; the newly sensitized immune cells are then reinfused back into the patient. In melanoma, this approach has caused 70% of tumors to regress.

The final analysis

Regardless of how effectively a vaccine causes tumor regression, patients and their physicians are most interested in its effect on survival. Also important is how use of a vaccine compares with the targeted therapies that have been developed. For cancer to become a truly chronic condition, manageable over the long term, a vaccine or treatment must be safe. Vaccines, as it turns out, are generally less toxic than chemotherapy or targeted agents. Immune-based treatments for cancer are still in their infancy, but if they are ultimately proven successful, their development would be well worth the effort.

Source:http://www.oncologystat.com/news-and-viewpoints/what_patients_are_reading/Search_for_a_Cancer_Vaccine_Beginning_to_Show_Promise.html

My take:Creating a “foreign” tumor

If you can get the tumor to shed antigenic peptide and then activate the T-cells using anti-CTLA-4 Blockage, I believe you will see the Melanoma survival rate expand and that Melanoma will become just a "chronic condition,manageable over the long term."






Take Care,

Jimmy B

Update on Topical Imiquimod ..It seems to be working!!.Melanoma..Jim Breitfeller

Update on Topical Imiquimod ..It seems to be working!!!!

Imiquimod: Unexpected Killer



How might imiquimod activate the apoptotic program in melanoma cells? Several pathways leading to the induction of apoptosis have been described over the last years. Schön et al started to examine the role of these different cell death pathways and first showed that imiquimod-induced apoptosis requires the activation of the "work horses" of apoptosis necessary for the unique phenotype of apoptotic cells, namely, the caspase family of proteases (Nicholson, 1999). A widely studied pathway for the induction of apoptosis is the "extrinsic" cell death pathway, when apoptosis is triggered from the outside of the cell by death receptors like TNF-R1, TRAMP, CD95, TRAIL-R1 and -R2, DR6, and EDA-R (Locksley et al, 2001).

Source:http://www.nature.com/jid/journal/v122/n5/full/5602304a.html

Imiquimod: Unexpected Killer


Take Care,

Jimmy B

Bristol's Cancer Bet!!! Melanoma ..Jim Breitfeller

Bristol's Cancer Bet

Robert Langreth, 07.23.09, 05:26 PM EDT
Cancer immunotherapy has mostly been a failure so far. With its $2.4B purchase of Medarex, the company wagers it has found a winner.

Bristol's Cancer Bet


Attempts to spur the immune system to kill tumors have mostly failed in trials. Now Bristol-Myers Squibb is betting billions that it can make immune-targeting therapies finally work against cancer.

Its $2.4 billion cash acquisition of the biotech firm Medarex ( MEDX - news - people ), announced late Wednesday, represents a giant gamble that immunotherapy will become the next big thing in cancer treatment. Medarex's lead drug, ipilimumab, now in a final-stage trial for advanced melanoma, doesn't target tumors directly at all. Instead it works by removing the brakes on the immune system so it can attack and kill the tumor.


Yahoo! BuzzIn recent years, evidence has built that the immune system can sometimes attack and kill cancer cells--sometimes--but that cancer finds ways to fight back and evade or blunt the attack. (See "Cancer Miracles") For some people with advanced cancer, ipilimumab may be just enough to trigger a full-fledged anti-tumor attack. Bristol-Myers Squibb ( BMY - news - people ) has been collaborating with Medarex for years but now will get full rights to the drug.

"We wouldn't be betting $2.4 billion in cash unless we were optimistic" it would work, said Bristol-Myers Chief Executive James Cornelius in a conference call. "This will not be a cure-all for all types of cancer" but it could be "complementary to therapies that are out there today." Medarex has other cancer immunotherapies in earlier stages of testing, as well as drugs targeting lupus, rheumatoid arthritis and inflammatory bowel disease.

Bristol's buy is a risky move because numerous treatments and vaccines that aim to stimulate the body against cancer have mostly failed. One of the few that has worked so far is an experimental prostate cancer vaccine from Dendreon ( DNDN - news - people ) that recently had good trial results. The immune system is one of the more complicated parts of the body and doctors are only beginning to understand its intricacies. Another immune-boosting therapy against cancer, the natural immune system protein interleukin-2, has been limited by severe side effects.

Most trials of ipilimumab to date have been in advanced melanoma, where a small percentage of patients have experienced spectacular long-lasting remissions, even as the drug appears to do relatively little for the majority. Why more patients don't respond is a subject of intense research at laboratories worldwide. Some patients get autoimmune side-effects.

My Comment:

They will only get Synergistic complete responses when they use ipilimumab in combination with IL-2. You also will have to have the right antigen to be presented.Timing when the drugs are introduced in the therapy plays a critical roll in the outcome of the immune response.






Take Care,

Jimmy B

Remember I said the Timing of the IL-2 Is Critical!!Melanoma..Jim Breitfeller

Remember I said the Timing of the IL-2 Is Critical!!Melanoma..Jim Breitfeller

Well that was base on my therapy and Melanoma experience.

Well, Last night I came across a paper that caught my eye.

Manipulation of Regulatory T-Cell Number and Function with CD28-Specific Monoclonal Antibodies

By Dr. Thomas Hunig*

Prof. Dr. Thomas Hünig
Institut für Virologie und Immunbiologie
Versbacher Str. 7
D-97078 Würzburg
Germany

So I email him in Germany for a copy of his paper. I received it this morning.


I now have hard facts that back up my theory.

This is tell me there is a feedback loop. By supplying extra IL-2 in the beginging of the activation event, you grow the cd4+ Tcells along with the Tregs. This is not what you want to do.



Everything is coming together rather well!!!!!

Look at the homing to the inflamed tissue!!!!! see both diagrams. The inflamed response is within 15 days. This is not a coincidence. I believe all the pieces are falling into place.

Take care

Jimmy B



Melanoma_Missionary

YESssssssssssssss!!! Confirmation of my Theory Melanoma.. Jim Breitfeller

Congratulations,

I think you may find our ASCO abstracts interesting this year. Especially the one that talks about the time dependent variability of immunoreactivity in patients with melanoma.

Take care,
Svetomir

The American Society of Clinical Oncology (ASCO) is the world's leading professional organization representing physicians who treat people with cancer.

Svetomir N. Markovic, M.D

Education:

Fellowship – Department of Internal Medicine; Division of Hematology, Department of Oncology
Mayo Graduate School of Medicine

Residency – Internal Medicine
Mayo Graduate School of Medicine

Medical College of Pennsylvania

Fellowship – Part-time Post-doctoral; Microbiology/Immunology, Pharmacology
Medical College of Pennsylvania

Ph.D. – Department of Microbiology/Immunology
Medical College of Pennsylvania

Areas of Research
Melanoma

Cancer Immunology and Immunotherapy Program
Clinical Immunology and Immunotherapeutics
Department of Immunology
Prostate Cancer Program
Translational Immunovirology and Biodefense Program
Academic Affiliations
Clinical & Translational Science Program
Immunology Program


Summary:

Translational immunotherapeutics of cancer focused on malignant melanoma and non-Hodgkin's lymphoma. This work includes development and clinical testing of: cancer vaccines; immune boosting agents; novel agents that reconstitute immunity in patients with cancer; and combination therapy directed at enhancing anti-tumor immune responses.





Yes Now I can say my theory holds water and just coming out in May/June at the ASCO
Meeting.I am trying to get this out to all the clinical Oncologists. So they can incorporate this into there trials. I hope I am not stepping on any Toes.



Jimmy B

cAN YOU sAY 1 PLUS 1 EQUALS TWO!!!!!!!!!! Melanoma..Jim Breitfeller

"Our NIH doc seems to think that TIL patients have a better response with this drug(CTLA-4) "possibly" than the general population."

PLUS!!!!!!!!!!!!

"I was told yesterday that the "Til Harvest" that MDA,(MD Anderson) is doing is seeing more response (positive) to patients that have had IL-2 prior to using their T-cell harvested cells."

EQUALS!!!!!!!!!!!!!!!!!!!!!!



I think this will give US ALL a fighting chance.

Signal 1 from anti-CTLA-4 blockage and antigen and T cell receptor

Signal 2 IL-2 therapy

Third signal "Danger Signal" the CTLA-4 15mg/KG Dose

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 (7–13). Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells (14). Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells (15, 16). 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 (17). 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, and IFN-γ provide a third signal that acts directly on T cells (18), referred to as the “danger signal” (19, 20). This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells (18).”

Source: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=300854


I CAN SEE THE LIGHT AT THE END OF THE TUNNEL!!!!!!!!!!!!!!!!!
jIMMY b

The Letter "Working on a Dream" Melanoma ..Jim Breitfeller

Dr. Luis Camacho, I am asking for your help. Based on my success, we need to propose a clinical trial. I have spent numerous hours researching my combination therapy. I believe this merits an investigation.

“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 (7–13). Therefore, this event depends entirely on appropriate antigen presentation, which is most efficiently provided by mature dendritic cells (14). Peripherally tolerant or “ignorant” self-reactive T-cell clones, once properly activated, may serve as tumor-specific effector T cells (15, 16).

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 (17). 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, and IFN-γ provide a third signal that acts directly on T cells (18), referred to as the “danger signal” (19, 20). This signal was found to optimally activate TH1 differentiation and lead to clonal expansion of T cells (18).”

Source: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=300854

On day 15 there inflammation around my axilla tumors.So all three signals were in place.


Source: The Maximum Propagation time was from ITOH ET AL.

Itoh, K; Platsoucas, CD; Balch, CMAutologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor [published J . Exp. MED. The Rockefeller University Press. 1988 Oct 1; Vol 168 October 1988 1419-1441

Source: http://jem.rupress.org/cgi/reprint/168/4/1419.pdf

If you look at the graph, High dose was inoculated at the maximum CD8+ T cell propagation. This IL-2 addition promoted the induction of effector function. At about the same time the CTLA-4 was almost out of my system base on the half life. This is why I had no autoimmune response side effects.

IL-2 is commonly used as an adjuvant in immunotherapy protocols. In addition to playing a critical role in survival of CD8 T cells, when presented at high levels to antigen-activated CD8 cells, IL-2 can also promote the induction of effector functions, such as granzyme B (gzmB) via STAT5 signaling, thereby functioning as a costimulatory molecule and also as growth factor.

"IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation1

Michelle L. Janas2, Penny Groves, Norbert Kienzle and Anne Kelso3 Cooperative Research Center for Vaccine Technology and Queensland Institute of Medical Research, Brisbane, Australia

“Granule-mediated cytotoxicity is one of the major mechanisms used by CD8+ T cells to eliminate harmful or foreign bodies, such as virus-infected cells, tumors, and allografts. After Ag recognition, activated CD8+ T cells release the contents of their cytotoxic granules into the extracellular space, where they are taken up by the target cell, and apoptosis is initiated (1). The cytotoxic granules contain a number of molecules, including the pore-forming protein, perforin, and serine proteases, known as granzymes. Perforin was originally thought to cause cell lysis by penetrating the target cell membrane (2), but recent work favors the theory that perforin functions by enabling the granzymes to escape from endosomes into the cytosol of the target cell (3, 4). Whatever its exact role, perforin is essential, because Ag-specific granule-mediated cytotoxicity is absent in perforin-deficient CD8+ T cells and NK cells (5).”Although the perforin and granzyme genes are known to be inducible, because a T cell must be activated before the cytolytic molecules are expressed at the mRNA or protein levels (13, 15), the signals responsible for regulating gene expression have yet to be identified. The exceptions are studies examining the role of the cytokine, IL-2. IL-2 has been shown to up-regulate perforin and granzymes A and B in human PBL (16), and binding sites for the IL-2-induced transcription factor, STAT-5, have been located in the perforin promoter region (17, 18)."


This is what I believed happen to me. I believe we need to investigate it. Since I am not Research Oncologist, I don’t know if anyone would take me serious. I went from 40 + nodulars in my lungs to NED and have been NED for two years.I believe we jump started my immune system.

Guess Who got In touch with me??Melanoma ..Jim Breitfeller

Hint: Mr. CTLA-4 Himself, Dr. Luis Camacho in Texas!!!!

Back In 2005:

On 10-24-2005 when I was first diagnosed with melanoma, I contacted Dr. Luis H. Camacho who was currently at MD Anderson.

Subject: Paper on Antitumor Activity

“Luis Camacho, My name is Jim Breitfeller and I have recently been diagnosed with melanoma will need some sort of Ontological therapy after my surgery. I ran across an abstract of yours (Antitumor activity in Melanoma and anti-self responses in Phase 1 trials with the anti-Cyctotoxic T Lymphocyte-Associated Antigen 4 Monoclonal Antibody CP-675,206) in the Journal of Clinical Oncology. Is it possible to get a copy of your paper? It can be emailed to the address below.”

Camacho response:

Dear James,
Thank you for your note. The CTLA4 antibodies in melanoma are currently under development and completing the approval process with the FDA (Phase II and Phase III). The overall response rates in my mind will be near 20-30% with a good number of patients attaining long term remissions. However, none of the programs are currently oriented to patients rendered NED (Stage III or IV). They are in fact for patients with advanced disease. From your brief introduction, I think your best options are to obtain an HLA typification and go for an adjuvant trial.

Please feel free to page me if you need further information. Pager is 713.404-5319
Best,

Luis
CP-675,206, a novel monoclonal antibody, enlists the immune system to fight advanced melanoma


Today:
Dear Jim,

Thanks for your note. You really refreshed my mind! I am glad things have worked out relatively well for you!. Did you get rid of your disease?. I am glad you are writing your story and hopefully inspiring a number of patients in dire need of hope. Let me know how can I help.

Kindest regards,

Luis


Now I can hopefully get Dr. Camacho to propose a Clinical Trial based on my success. This my Dream. As Bruce Springstein "I am working on a Dream".

And If I have the research right it may be one of the paths to the "YELLOW BRICK ROAD"

Jimmy B

Comparison Between the two Therapies Melanoma..Jim Breitfeller

This is all base in the reseach paper from 1988.4. Itoh, K; Platsoucas, CD; Balch, CMAutologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor [published J . Exp. MED. The Rockefeller University Press. 1988 Oct 1; Vol 168 October 1988 1419-1441http://jem.rupress.org/cgi/reprint/168/4/1419.pdf
Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor


And YES, Dr. Kirkwood's therapy is only one Data point.

But I am Happy to be that data point!!!!!
Jimmy B

As Paul Harvey would say, "Now Back to the Rest of the Story" Melanoma .. Jim Breitfeller

The Orchestration of an Inmmune Response Unrehearsed -Continued-

Day 29- 10/11/06, A couple of days ago, Dee noticed two new growths on my back. Iwas hoping for the best. Anyway, we got confirmation from the Hillman Center that it is 2 new tumors growing. This really stinks. I think it is time to take out the “Weed be Gone”. This is not what I was hoping to hear. It was decided that the CTLA-4 blockage therapy was to be terminated. My CD4+T cells were just about at maximum propagation.

Dr. Kirkwood, decided that the next line of defense would be Interleukin-2 (IL-2).

Results of early PROLEUKIN® IL-2 Clinical Trials

Year received FDA Approval 1998

Number of Patients 270 patientsNumber of Trials 8
Response In 16% of the patients, tumors shrank or disappeared as a result of PROLEUKIN® IL-2 therapy.

In 6% of the patients, the tumors disappeared completely.

Results From these trials, it was determined that a patient whose tumors completely disappeared from the treatment remained cancer-free for a median of 4.9 years.

I needed to washout the CTLA-4 blockage and have some test run before I would be accepted into the next trial. We know from the PK studies that it would take 42 days to eliminate the antibodies from my system.

Day 43-10/25/06, I got the results back from the Scans and it wasn’t good. The cancer is spreading in my lungs quite rapidly according to the CT scans. There are now over 40+ nodules ranging from 15 mm down to <>Day 50- 11/1/06, the first cycle of High dose Interleukin-2 (IL-2). It just so happen to be the maximum propagation of the CD8+ T cells. All of the anti-CTLA-4 is washed out. We also, most likely have the most CD4+ T reg cells. These are the cells that help regulate the immune response so it doesn’t go into overdrive and cause an autoimmune response.

If we reset the clock for the second therapy (LI-2), then we can follow the activation of the CD8+ T-cells. My body has become a big Erlenmeyer flask. Erlenmeyer flasks are used in microbiology for the preparation of microbial cultures.

So on day 50- 11/1/06, we innocuated my body with IL-2 – a growth factor. So based on the Itoh study, I should be activating the CD8+ T-cells into a mature state (TILs and LAK cells.) It should take roughly 50 days they would be at there maximum growth phase.

In Itoh’s study the cultures were supplemented every 5 days by replacing half the cultured medium with fresh medium containing (IL-2) as one of the supplements. My IL-2 additions were every 21 days. (Need the dose Information)

On 78th day 11/29/06, the second cycle of IL-2 was administered. It was pushed back a week due to the Thanksgiving Holiday. I completed 8 doses which is the average that patients can withstand.

On day 93 12/14/06, I had another CT scan. I am trying to recover between cycles.

On day 98 12/19/06 we got the CT Scan Results: What a Christmas Present!!!!!! The tumors were shrinking!!!!!!!

Melissa’s Note:

I'm Christmas shopping.....but Heather called me with the results....I AM SOOOOO HAPPPY FOR YOU!!!!!!!!!!!!! YIPPPPPEEEEEE!!!!!!! Hope you have a wonderful holiday, and I'll see you soon :) :) :) :) Melissa

As you can see, the timing and the players of this Orchestration all fell into place. A single Bullet of Monoclonal antibodies started the whole sequence of events which lead to the restarting of my immune system. Without that bullet, there would have been no "Danger Signal"

"Melanoma and the Magic Bullet (Monoclonal Antibodies)"

This is dedicated to Leanne Schmall who lost the fight to the Beast, Melanoma

Jimmy B

Jimmy B

The Orchestration of an Inmmune Response Unrehearsed Melanoma..Jim Breitfeller

The Orchestration of an Inmmune Response Unrehearsed

In 2006, after two fail attempts (Interferon and Dacarbazine with Patrin) to stop the progression of my melanoma, I was able try CTLA-4 Blockage. It was one of my first choices, but due to protocol, I had to try the FDA approved therapy first. I had researched this monoclonal antibody. On 10-24-2005 when I was first diagnosed with melanoma, I contacted Dr. Luis H. Camacho who was currently at MD Anderson.

Subject: Paper on Antitumor Activity

“Luis Camacho, My name is Jim Breitfeller and I have recently been diagnosed with melanoma will need some sort of Ontological therapy after my surgery. I ran across an abstract of yours (Antitumor activity in Melanoma and anti-self responses in Phase 1 trials with the anti-Cyctotoxic T Lymphocyte-Associated Antigen 4 Monoclonal Antibody CP-675,206) in the Journal of Clinical Oncology. Is it possible to get a copy of your paper? It can be emailed to the address below.”

Camacho response:

Dear James,

Thank you for your note. The CTLA4 antibodies in melanoma are currently under development and completing the approval process with the FDA (Phase II and Phase III). The overall response rates in my mind will be near 20-30% with a good number of patients attaining long term remissions. However, none of the programs are currently oriented to patients rendered NED (Stage III or IV). They are in fact for patients with advanced disease. From your brief introduction, I think your best options are to obtain an HLA typification and go for an adjuvant trial.

Please feel free to page me if you need further information. Pager is 713.404-5319
Best,

Luis

CP-675,206, a novel monoclonal antibody, enlists the immune system to fight advanced melanoma

Some Positive Test results of the CTLA-4

"Early testing of an experimental human monoclonal antibody showed a striking benefit in patients with advanced melanoma, say researchers at The University of Texas M. D. Anderson Cancer Center, who presented their findings at the annual meeting of the American Society of Clinical Oncology. Of 39 patients given a single injection of CP-675,206 (known as CP-675), tumors disappeared in three patients, shrunk in a fourth patient, and cancer stopped growing in five other patients. These responses have remained since their initial treatment, which ranged from 13 to 28 months ago.

Most of the patients in the trial had advanced melanoma, which has a median survival of less than a year, says the study's principal investigator, Luis Camacho, M.D., MPH, assistant professor in the Department of Melanoma Medical Oncology.

"We were very pleasantly surprised to find such objective antitumor responses in a Phase I clinical trial, which is designed to find the ideal dose and to look for side effects," says Camacho. "These results are very early, but they are encouraging to us because there are no good agents available to treat melanoma once it has spread."

Source: Laura Sussman from (ASCO) American Society of Clinical Oncology

At the time of the request, I was not at the correct stage but I knew that this might be the path of the future. I did contact him and we discussed my options at that time. I was just learning the ropes.

On 9/3/06 I contacted Dr. Rosenberg just in case I needed a back up plan if the CTLA-4 blockage did not work. At that time I did not know I was the wrong HLA-02 type for Rosenberg’s trials.

“I am Contacting Dr. Steven A. Rosenberg at the National Cancer Institute in Bethesda, Maryland.

He is the lead the researcher on the Gene Therapy Trials.
Log onto the CBS website for the story!!!!!!
http://www.cbsnews.com/stories/2006/08/31/health/main1955526.shtml
The research team recently applied to the Food and Drug Administration (FDA) to try the new cells in about 100 patients. The FDA is expected to respond to the request by mid-September.

Dr. Rosenberg, I just got the news of your Gene Therapy Experiments. The initial results look somewhat promising. I applauded you and your team for making great strides in the cure for melanoma cancer.

I am a cancer patient (48 yrs. old) under the care of Dr. John Kirkwood at the Hillman Cancer Center at the University of Pittsburgh. I have gone through a wide incision, lymph nodes removal, Interferon therapy, and Dicarbazine therapy without success. I am presently on track to start a clinical trial with CTLA-4 monoclonal antibodies September 13, 2006. I have some tumors on my right side of my back and some in each lobe of my lungs. I would like to be considered for your next round of Gene Therapy in the coming months if I have no response to the CTLA-4 treatment. Please let me know if you would need a copy of my medical records to date.

Thanks again for the great work you are doing and I hope to hear from you in the near future.

Best Regards,

Jim Breitfeller

On 9/5/06 I received a call from Dr. Rosenberg’s office this morning while I was at Dr. Marino’s office. Kathy Morton (Research Nurse) contacted me by phone and asked a few questions about my health. She went on to say if I go with the CTLA-4 therapy, it would take about 2 months to washout before I could try the Gene Therapy. They would also have to do a colon biopsy to check the colon for any adverse conditions from the CTLA_4. She then gave me her direct phone number if I want to pursue the gene therapy at a later date.

So, on 9/13/06 (day 1)I had my first and only infusion of anti-CTLA-4 monoclonal antibodies. This was done as an outpatient procedure. Anti-CTLA4 monoclonal antibodies block the ability of CTLA4 to down-regulate T cell proliferation. The theory behind this therapy is that by decreasing the inhibitory signal, there will be a subsequent increase in the number of activated T-cells available, to improve the ability of the T-cells to recognize melanoma cells as non-self.

Before we can go any further, we need to know the clinical pharmacokinetics (pk)of anti-CTLA-4 monoclonal antibodies. Base on published papers, the predicted half-live of the antibody is around 3 weeks.11 This means your body will eliminate half the dose that was infused in you in about 21days. So, in 42 days or there about, the drug is completely gone from your system.

I started my CTLA-4 treatment at 9:15 am at 100 ml/hr and I had 500 mls hanging on my rack (Miss Daisy). I call the rack Miss Daisy because I have to take it with me where ever I go which includes the bathroom. I am driving Miss Daisy!! This will take us to 3:15 pm and then they draw blood for a pk study an hour later. So, we won’t get out until about 4:30 pm and home until 10:00 pm.

Day 7-9/19/06 “Along with the fatigue, my muscles ache like they have lactic acid in them”. Is this an indication of something? All immune cells begin as immature stem cells in the bone marrow.

Day 15 -9/27/06 about half the CTLA-4 antibodies are depleted. It appears that the CTLA-4 has stimulated my immune system. In the pass week, I noticed that there was redness around the area where my tumors are located. Also it is becoming quite tender in that area. This is Great news!!!!! It appears that the treatment my have kick started my immune system. The only way we will know for sure is another CT scan. That is not scheduled until November 23rd.

I sure hope this isn’t a false positive. Anyway, they gave me an antibiotic just in case it is an infection.

This inflammatory response 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 cells12.

With this clonal expansion of the T cells and the secretion of IL-2, The Immune system is gearing up to make an assault on the foreign invaders, the tumors.

In 1988, a paper was published Autologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor by Itoh and Colleagues.4

In their studies, they propagated (TILs) Tumor infiltrate lymphocytes cells from 12 Metastatic Melanoma patients. They preformed kinetic growth studies in IL-2 and even broke it down three Surface markers (CD3,CD4 and CD8). The results are as follows:

The average maximum propagation was 43 days. (N=12)
The average maximum propagation for (lung, Axilla) was 40 days (n=3)
The average maximum propagation for (CD3) was 78 +/- 11 days (n=12)
The average maximum propagation for (CD4) was 33 +/- 10 days (n=12)
The average maximum propagation for CD4 (lung, Axilla) was 26 days (n=3)
The average maximum propagation for (CD8) was 49 +/- 17 days (n=12)
The average maximum propagation for CD8 (lung, Axilla) was 57 days (n=3)

Base on the above data, it would take about 49 days for my activated T cells to reach maximum propagation.

4. Itoh, K; Platsoucas, CD; Balch, CM
Autologous Tumor Specific Cytotoxic Lymphocytes in the Infiltrate of Human Metastatic Melanomas Activation by Interleukin 2 and Autologous Tumor Cells, and Involvement of the T Cell Receptor [published J . Exp. MED. The Rockefeller University Press. 1988 Oct 1; Vol 168 October 1988 1419-1441
http://jem.rupress.org/cgi/reprint/168/4/1419.pdf


11. H. F. Wang1, J. M. Lovering1, R. M. Shepard1, D. Zhang2, T. A. Smolarek1, J. W. Findlay3 1Pfizer Inc, 2FDA, 3Gilead Sciences Inc; Pharmacokinetics of Tremelimumab, a Cytotoxic T Lymphocyte-Associated Antigen 4 (Ctla4) Blocking Monoclonal Antibody, in Nonhuman Primates
http://www.aapsj.org/abstracts/NBC_2008/NBC08-000658.PDF

12. Holger N. Lode,1 Rong Xiang,1 Ursula Pertl,1 Elisabeth Förster,2 Stephen P. Schoenberger,3 Stephen D. Gillies,4 and Ralph A. Reisfeld1; 1The Scripps Research Institute, Department of Immunology, La Jolla, California, USA2University Children’s Hospital Vienna, Vienna, Austria3La Jolla Institute for Allergy and Immunology, Division of Immune Regulation, San Diego, California, USA4Lexigen Pharmaceuticals Corp., Lexington, Massachusetts, USA Melanoma immunotherapy by targeted IL-2 depends on CD4+ T-cell help mediated by CD40/CD40L interaction; J Clin Invest. 2000 June 1; 105(11): 1623–1630. doi: 10.1172/JCI9177 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=300854#B13#B13



To be continued!!!!!!



Jimmy B

I am back from my Punch Biopsy !!!! Melanoma .. Jim Breitfeller

Before I can be included in the Rose Bengal Clinical Trial, They want to know if the lesion is Melanoma. So, here are some pictures:

This was taken before CTLA-4 & IL-2 therapy.


Taken by my Wife (Dee) on 1/17/2009

Taken by my Wife (Dee) on 1/24/2009
5 days of 2% Mupirocin oinment twice a day

10 days of 2% Mupirocin oinment twice a day

You can see where my wide incision was and the Reoccurrence in the wide incision.One thing that is different, there is no height to the lesion. So is it stuck in the radial growth phase? Has it mutated more? Hopefully the pathology will tell us.


So, Dr. Richardson under the direction of Dr. Marc Brown did the punch biopsy. I did not feel a thing because there is no nerves there due to the surgery. They also froze some skin on mt chest that looked like it could be some basal cell. So Now We wait and see if it is indeed Melanoma.


Jimmy B

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 3 of 5)

Abrogation of CTLA-4 in patients produces side effects known as "immune-related adverse events" (IRAEs). IRAEs are auto-inflammatory and may represent a breaking of tolerance to self-antigens.[16,17] The most common IRAEs are rash, colitis, and hepatitis. Other types of inflammation -- hypophysitis, pancreatitis, and sarcoid -- are more rare. IRAEs appear to be associated with tumor regression in patients with renal cell cancer and metastatic melanoma,[12,17-19] and a similar phenomenon may be observed in patients with prostate cancer.[14] There also appears to be a correlation between IRAEs and prolonged time to relapse in patients with resected high-risk melanoma.[12,17-19] The kinetic onset of IRAEs is highly variable and is likely dependent both on peak dosing and area under the curve of the drug. Similarly, the timing of the onset of antitumor responses can be variable and may be prolonged for weeks after cessation of ipilimumab[20]
(J Weber, unpublished data, 2007).

If these immunomodulators and others like them -- CD40 agonistic antibody, anti-41-BB antibody, and programmed death (PD)-1 antibody, which are entering early-phase clinical testing -- are approved for cancer treatment, then understanding the kinetics of antitumor responses, their relationship to IRAEs, and how to manage and minimize IRAEs will take on great importance.

Ongoing and Completed Trials With Ipilimumab and Tremelimumab

Ipilimumab has been used as a monotherapy or in combination with other therapies including chemotherapy, vaccines, and cytokines. In an initial phase 1 trial,[21] 17 patients with malignant melanoma received a single intravenous dose of ipilimumab 3 mg/kg. The drug was well tolerated, and there was evidence of immunologic and antitumor activity. In another phase 1 trial, Hodi and colleagues[13] reported that a single dose of ipilimumab 3 mg/kg may have increased antitumor immunity and induced necrosis in biopsied tumors in patients with metastatic melanoma who were previously vaccinated. No serious adverse events were noted in the 7 patients who received ipilimumab in that trial.
Because of the known mechanism of action of ipilimumab and experience in murine models, an important goal has been its evaluation in combination with antitumor vaccination. Attia and colleagues[12] reported that ipilimumab (3 mg/kg every 3 weeks or a 3-mg/kg initial dose followed by 1 mg/kg every 3 weeks) plus a peptide vaccine resulted in 2 complete responses (CRs) and 5 partial responses (PRs) among 56 patients with previously treated and progressive stage IV melanoma. The CRs were ongoing at 30 and 31 months, and 3 of the PRs continued at 25, 26, and 34 months. The remaining 2 PRs lasted for 4 and 6 months.

A trial is ongoing with ipilimumab plus a multipeptide vaccine in the adjuvant setting,[20] which includes patients with resected stage IIIC/IV melanoma and no evidence of disease. After a median follow-up of 12 months, 6 of 25 (24%) treated patients had relapsed. Patients who relapsed were managed either surgically or with biochemotherapy, and all were alive at the time of the report. Subsequently, 4 patients have died at a median follow-up of more than 2 years, but 19 are still free of disease. Time to progression is associated with development of IRAEs (J Weber et al, unpublished data, 2007).

Ipilimumab has also been administered in combination with cytokines. Maker and colleagues[22] reported data from a trial of ipilimumab 0.1-3 mg/kg every 3 weeks with IL-2 in 36 patients with advanced melanoma. Three patients (8%) sustained a CR and 5 (14%) had PRs, yielding an overall objective RR of 22%. Responses occurred in 1 of each of 3 patients treated with ipilimumab at 0.3, 1, and 2 mg/kg, and in 5 of 24 patients treated at 3 mg/kg. Six of the 8 responders had ongoing responses at follow-up periods of between 11 and 19 months.

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 2 of 5)

A method to my Madness

As you can see from above I tried Interferon, dacarbazine (DTIC), Then a novel new agent called CTLA-4, and then onto IL-2 (Interlukin-2).

The use of a combination of IL-2, other immunotherapy agents, and chemotherapy, known as biochemotherapy, has been shown to result in high response rates (RRs) in patients with stage IV melanoma, but long-term survival without recurrence occurs in less than 10% of patients.[7] Biochemotherapy has not been shown to prolong survival beyond that seen with chemotherapy alone, which has averaged only 7 to 8 months. Therefore, a reasonable consensus is that patients with unresectable stages III and IV melanoma should be referred to a clinical trial as the first treatment for metastatic disease. More than ever before, those patients have access to a broad variety of agents --both targeted biologic drugs and immunotherapy compounds -- that have shown promise in treating unresectable disease.
The landscape for the development of new drugs for the treatment of patients with metastatic and resected high-risk melanoma is more promising than at any time in recent memory. The understanding of signaling pathways at the biochemical and molecular level and the identification of new immunoregulatory receptor-ligand pairs associated with outcome in patients with metastatic melanoma are paving the way for new drug development. A number of novel targeted and biologic agents (see below) are showing promise. A new biologic agent, as well as 2 new immunotherapeutic drugs now in registration trials, have the potential to be the first agents approved by the FDA for use in patients with stage IV melanoma in over a decade.
Potential New Agents for the Treatment of Melanoma
Human Antibodies Directed Against Immune Regulatory Molecules
Human antibodies directed against immune regulatory molecules such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) induce tumor regression and improve long-term survival in tumor-bearing mice. Early clinical studies in patients with melanoma have shown that disease stabilization and prolonged survival can be achieved by manipulation of the immune system.[8,9] CTLA-4 antibodies are currently being tested in phase 2/3 trials in melanoma and phase 1/2 trials in other tumor types. Currently, 2 human antibodies are in clinical testing: ipilimumab (MDX-010) and tremelimumab (CP-675206). Although the 2 agents have similar pharmacokinetic properties, tremelimumab has a 3-week half-life, which is slightly longer than that of ipilimumab.
As you can see, Dr. Kirkwood and I wanted to induce tumor regression by using my own immune system. If we could get my immune system to recognize the tumors as foreign, then we might have a fighting chance. So we decide to try the CTLA-4 Therapy,
Antitumor response with prolonged time to progression has been seen in patients with melanoma who have received either of the CTLA-4 antibodies,[10,11] and durable antitumor responses have been observed with ipilimumab in patients with melanoma,[12] ovarian cancer,[13] prostate cancer,[14] and renal cell carcinoma.[15] Of note, antitumor responses may be characterized by short-term progression followed by delayed regression.
An important, possibly unique, clinical characteristic of anti-CTLA-4 antibodies is that the duration of clinical response -- and even stable disease -- is often quite prolonged.

Novel Treatment Approaches For Patients With Metastatic Melanoma (Page 1 of 5)

A method to my Madness

* When I first started out trying to figure out what therapies I should try, Dee and I worked with Dr Kirkwood and developed a plan of attack (a flow diagram). We put together if and than statements to create a path forward. Coming from a research environment, this made the most practical sense.
So here is my path.

* Most of information was taken from an article written by Adil I. Daud, MDJeffrey S. Weber, MD, PhD entitled:

* “Novel Treatment Approaches For Patients With Metastatic Melanoma”

* Release Date: August 30, 2007

Introduction

According to the American Academy of Dermatology, an estimated 108,230 new cases of melanoma will be diagnosed in the United States in 2007, including 48,290 in situ and 59,940 invasive cases.[1] Invasive melanoma is the fifth most common cancer in men and women. About 8000 deaths from melanoma are expected in 2007 in the United States.[1]

Melanoma is a cancer of the melanocyte, a long-lived pigment-producing cell normally found at the dermo-epidermal junction within the skin. During the process of transformation of melanocytes to melanoma, histologic and clinical changes occur.[2] The initial stage of transformation can result in an atypical or dysplastic nevus. The next stage is the so-called epidermal radial growth phase (RGP) melanoma, which involves proliferation of the transformed melanocytes in the epidermis. This is followed by an invasive RGP melanoma wherein the tumor cells invade the dermis. In the next phase, the vertical growth phase, melanocytes proliferate in the dermis and are competent for metastatic invasion. Finally, the metastatic phase is characterized by invasion of lymph nodes and distant organs.

Based on a rigorous statistical analysis of a large sample of patients with melanoma, the American Joint Committee on Cancer proposed revised staging guidelines in 2002. These guidelines are useful for clinical management of patients and for analyzing clinical trial data discussed in this review.[3,4]

Stages I and II are melanomas that are localized to the skin, at varying depths of invasion:

stage III includes patients with regional recurrence and nodal spread of disease, and stage IV patients have distant metastatic spread of melanoma.

Currently, 3 drugs are approved for the treatment of metastatic melanoma:

dacarbazine (DTIC), hydroxyurea, and interleukin-2 (IL-2).

None has ever been tested in a randomized phase 3 trial against a control and been shown to prolong survival. DTIC and hydroxyurea were approved by the US Food and Drug Administration (FDA) more than 20 years ago and would be unlikely to meet current standards for FDA approval. The only approved immunotherapy for melanoma, IL-2,[5] is a toxic agent employed in a complex regimen used by a restricted number of centers in the United States today. Practice guidelines promulgated by organizations such as the National Comprehensive Cancer Network (NCCN) indicate that entry into a clinical trial is an acceptable standard of care for patients with newly diagnosed stage IV melanoma.[6] In fact, the NCCN decision tree for patients with stage IV melanoma with multiple metastases indicates that a clinical trial is the first choice, followed by DTIC or IL-2; lower priority choices include DTIC with other agents in combination. For patients with a small volume of disease, a watch-and-wait plan is considered acceptable, an admission that the armamentarium of drugs for metastatic melanoma is deficient.