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

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

New melanoma treatment -- a turning point against cancer?

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

~Charles Darwin~

Take Care,

Jimmy B

Ipilimumab update Melanoma..Jim Breitfeller

Jim,

First, you should know that you have a great site. I read multiple entries in your blog and found them all both educational and heartfelt. It is so great what you are doing, educating others while offering hope and strength for them and their families during their challenging times. I am so sorry for the loss of your brother and that now you yourself suffer from Melanoma. I have seen first hand the destruction that this fierce disease can do to a person but I have also seen how a great deal of faith and medical miracles can bring hope to the hopeless. That is why I am personally so excited by Ipilimumab, or IPI. My friend Beca was selected for a 'compassionate' study with the IPI between pre and post FDA approval of the drug and actually starts her second round today! We are all hoping this miracle drug can work it's magic on her. You said it best, "The best Melanoma patient is an active participant in his or her treatment" and I could not agree more. You are a perfect example of this.




I think you might be interested in this video. It talks more about Ipilimumab and includes the side effects of possible arthritis etc and the fact that the drug is choosy as to who it will work for, only 20 - 30% of it's patients. However, and I'm sure you will agree, this is still a huge and exciting breakthrough. I hope you see the relevance of this and that you will consider embedding it into Melanoma Missionary. The best of luck to you and your family as you continue this challenging climb. I hope that this email finds you well.




Please let me know if you have any questions,


Haley

Jim's Response

Haley, I believe I know why Ipi only responds in 20-30%. I have been researching this for a while and the missing link is the "Danger Signal". All the pieces of the Melanoma are not there yet, I am closing in on it. I believe we can increase the response rate by combinatorial Therapy with Ipi and IL-2. Dose and scheduling of the drugs play important part of this Orchestration.

If you Look back at some of my posts and research papers, You will see the Light at the end of the tunnel.

Please keep me posted about your friend. Make sure that they (The Oncologist) gets the ALC Absolute Lymphocyte Count before, and during your friends treatment. If the counts rise by a factor of about two, it may be an indication that the Ipilimumab (Anti-CTLA-4 Blockade is working. It would help activate the CD8+ T-cells (CTLs) Cytoxic T Lymphocytes.

Best Regards,

Jimmy B

pp

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

Jimmy B

Unleashing the Immune System to Destroy Melanoma..Jim Breitfeller

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




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

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

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

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

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


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

~Charles Darwin~
Take Care,
Jimmy B

Drug, Ipilimumab boosts survival in major skin cancer study.Melanoma .Jim Breitfeller

Drug boosts survival in major skin cancer study
By MARILYNN MARCHIONE (AP) – 50 minutes ago

Check our my paper called Melanona and the Magic Bullet (Monoclonalantibodies)
Melanona and the Magic Bullet (Monoclonalantibodies)


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


CHICAGO — Researchers have scored the first big win against melanoma, the deadliest form of skin cancer. An experimental drug significantly improved survival in a major study of people with very advanced disease.

The results, reported Saturday at a cancer conference, left doctors elated.

"We have not had any therapy that has prolonged survival" until now, said Dr. Lynn Schuchter of the Abramson Cancer Center at the University of Pennsylvania, a skin cancer specialist with no role in the new study or ties to the drug's maker.

The drug, ipilimumab, (ip-ee-LIM-uh-mab), works by helping the immune system fight tumors. The federal Food and Drug Administration has pledged a quick review, and doctors think the drug could be available by the end of this year.

"People are going to have a lot of hope and want this drug, and it's not on their doctors' shelves," although some may be able to get it through special programs directly from its maker, Bristol-Myers Squibb Co., Schuchter said.

The study involved 676 people around the world with advanced, inoperable melanoma who had already tried other treatments — a very grim situation. They were given one of three treatments: ipilimumab by itself, with another immune-stimulating treatment, or the immune-stimulating treatment alone.

After two years, 24 percent of those given the drug alone or in combination were alive, versus 14 percent of those given just the immune-stimulating treatment.

Average survival was 10 months with ipilimumab versus just over 6 months for the others, which worked out to a 67 percent improvement in survival for those on the drug, said one of the study's leaders, Dr. Steven O'Day of the Angeles Clinic and Research Institute in Los Angeles.

Doctors hope the drug can provide more benefit if given earlier in the course of the disease and to less sick patients.

Ten percent to 15 percent of patients on ipilimumab had serious side effects related to the drug's actions on the immune system. Most were treatable with high doses of steroids, but 14 deaths were thought to be related to the treatment. That's still far fewer than deaths due to the cancer.

The study was funded by Bristol-Myers and Medarex Inc., a company that co-developed the drug and was bought by Bristol-Myers last year. A spokeswoman said Bristol-Myers has not yet set a price for the drug, but similar treatments for other cancers cost several thousand dollars a month or more.

Results were reported at the American Society of Clinical Oncology's annual conference in Chicago and published online by the New England Journal of Medicine.

Melanoma is the most serious form of skin cancer. Last year in the United States, there were about 68,720 new cases and 8,650 deaths from the disease. Worldwide, more than 50,000 people die of melanoma each year.

___

Online:

Cancer meeting: http://www.asco.org




“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care
,Jimmy B

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

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

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

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

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





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

~Charles Darwin~

Take Care,
Jimmy B

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

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

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

Meeting: 2010 ASCO Annual Meeting



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

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

Session: Melanoma/Skin Cancers

Type: General Poster Session

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

Location: S Hall A2

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





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



Abstract:

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

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


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


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


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

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





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



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

~Charles Darwin~

Take Care,
Jimmy B

Smart bombing Melanoma..Jim Breitfeller

Smart bombing Melanoma

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

~Charles Darwin~

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

Source: http://www.cellbiolint.org

Chemotherapy

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



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


Source: NCI



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

~Charles Darwin~

Take Care,
Jimmy B

'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

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

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

Study Start Date: February 2003

Detailed Description:

OBJECTIVES:

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

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

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

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

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

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

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

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

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

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

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

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

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







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







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

Thanks for you time

Best regards,

Jim Breitfeller

Melanoma and The Magic Bullet (Monoclonal Antibodies)


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


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




Take Care,

Jimmy B

A note To Dr. Keith Flaherty.. Combinatorial Therapy..Melanoma..Jim Breitfeller..2-25-2010

"One year, Dr. Flaherty thought, when he heard the news. Certainly no triumph. But it was something. Something to be built on.

Novartis and Bristol-Myers had agreed to schedule teleconferences for later in the month to talk about combination trials. He checked the dates on his electronic calendar. A meeting with Pfizer was also pending."



Dr. Flaherty,

As early as May of 2009 I had come to the conclusion that the drug companies must work togther to come up with a stabilization/cure.

As a fellow researcher and Blogger, What can I do to help convince the pharma this it is in their best interest to work together. It would be a win, win for all, including the Patients like myself.

Keith, Please let me know what I can do to Help?

Best regards



Jim Breitfeller





Friday, May 8, 2009

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space Melanoma.. Jim Breitfeller

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space.

With ASCO Annual meeting coming up at the end of May, I believe that there will be some excitement around monoclonal antibodies. In particular, anti-CTLA-4 blockage treatment will be under the spotlight. What will the overall survival rates look like? Well, speaking from my experience, anti-CTLA-4 has prolonged my life for over 27 months where as a stage IV Patient, I was given 6 to 9 months. This could not have happen with out the extra help from Interleukin -2.

See, once the CD4+ T-cells activated, they need to grow and cross-prime the CD8+ T-cells. While activated T-cells secretes IL-2 at a certain concentration to help promote proliferation of the CD4+ T-cells. If there is too much IL-2 at the beginning of the immune response, I believe that the ratio of CD4/CD8/CD3 would be altered causing
the Tregs (CD4+ CD25 fox P3) to gain the upper hand of suppression of the immune response. A subset of CD4 + cells called CD4 + CD25 + regulatory T (Treg) cells that expresses Forkhead box P3 (Fox P3).

With just adding Anti-CTLA-4 first, It has been reported that it suppresses the T regs and pushes the balance towards an immune response. Once the immune response is in progress, the CD4+ T-cell is needed to co-stimulate the CD8+ T-cell. 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.

Once the CD8+ T-cell is activated, and is cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

This is why we the patients need the Pharmacitical companies to work together. Each therapy will not work alone as a single agent. The response rate are 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 right for humanity”




Melanoma and The Magic Bullet (Monoclonal Antibodies)




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~

Braf PLX 4032 drug stopped working for first patient!!!Melanoma..Jim Breitfeller

This really crushes me. I was hoping this would be the beginning of the end for melanoma. Maybe it will with time and more research though.

I am not saying this will apply to anyone or everyone, but I think it is important that everyone needs to read this.

From MIF: Anyone currently on clincial trial of PLX 4032 or RO5185426 (jenniferslatton)

Posted: 3:20:38 pm on 1/27/2010 Modified: 4:12:04 pm on 1/27/2010

My 39-year-old husband is (as far as I know) the first U.S. patient to be in the Phase II BRAF-inhibitor trial funded by Roche Labs (partnering with Plexxikon). This trial uses the drug alone, without an arm that might include chemotherapy drugs (like the Phase III). He is on 960 mg twice aday of the drug, the highest tolerated dose. We are being treated at Moffitt in Tampa.

Clint began the trial the first week of October, about 15 weeks ago. We were astounded with the positive results and almost non-existent side effects (loss of body hair and mild muscle fatigue). That is, until last week, when the drug (PLX 4032/RO5185426) seems to have abruptly stopped working.

After much research we are learning that this is perhaps not an unexpected response. From my most recent reading it seems that for patients who are positive for the BRAF mutation (70% of melanoma patients), the BRAF-inhibitor may be necessary but not sufficient to create long-term effects. In my husband's case, we had genetic testing that determined the only mutation of note that could cause melanoma is the BRAF V600E mutation. But once he began the BRAF-inhibitor, the cancer seems to have created a new pathway around the drug. We will know shortly whether my husband's body has created new mutations and if so, which ones.

We are therefore, scrambling to find a new study that uses a combinatorial therapy of BRAF-inhibitor and MEK/RAS inhibitor (depending on what, if any, new mutations Clint has). I believe this combo therapy is likely to be the new frontier, and is already being studied in many places, including Australia and England. There is a combinatorial trial preparing to open in Nashville, TN, and I've got a call into their office to find out when. Now that the BRAF-inhibitor seems to have stopped working for my husband, we are in a race against the clock to once again stop his extremely aggressive, fast-moving disease.

In no way do I wish to "pull the rug out from under" any of you who are fortunate enough to be a patient on a BRAF-inhibitor trial. It has been an amazing drug! But I want to make sure we get our experience out there because we were very frustrated to not be given full disclosure about the likelihood of the disease finding new pathways. We had specifically asked our oncologist about a Plan B if the drug stopped working and he was dismissive of our question.

Now that we are in this scary place of seeing the disease quickly progress again, we have learned that the melanoma is now in his brain. This precludes Clint from most other clinical trials. If we had not let our guard down and had been looking ahead to combinatorial therapies, it would have made a big difference.


http://forum.melanomaintl.org/toastforums/toast.asp?sub=show&action=posts&fid=4&tid=9190

This is an indication that over time, Melanoma can mutate and change pathways to escape the immune system. As doctor's search for a cure, the BRAF therapy may end up as a "bridge therapy". Bascially something to fill in why they continue to look for more treatments.

I myself believe that the best way to overcome Melanoma is to use your own immune system.It can be done using a combination approach. Interferon,DTIC,Patrin-2,radiation,Anti-CTLA-4 and Interluekin-2. It is like a bicyle lock, you have to know the combination and proceed in the right order. The number of turns to the right or left corresponds to the doses and concentration.

Here is the combination, Good Luck!!!!!




Take Care,

Jimmy B

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

"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

Tumors as elusive targets of T-cell-based Active Immunotherapy..Melanoma..Jim Breitfeller

Dr. Herlyn, I been researching my successful Melanoma treatment and came across a research paper of yours “Tumors as elusive targets of T-cell-based active immunotherapy”. It postulates the mechanism underlying is the Antigen-Specific T-cell base immunotherapy can result in a complete response if activated appropriately. I believe that you diagram was right on target. My therapy was three clinical trials that followed your proposed mechanism. I did DTIC + PaTrin-2 to shed the right antigenic protein. Then I used Anti-CTLA-4 blockage to activate CD4+ T-cells and suppress the Tregs. IL-2 HD was added to help differentiate the T-cells and maintain there function and survival. Timing and dosing concentration played a major factor in breaking the balance of the tumor’s microenvironment. During my therapy I did get an inflammation response leading to a complete response.



Attached is a draft of what transpired and the dosing and timing. I believe this information might be very helpful in your research.
(See My Shared files)



"Melanoma and the Magic Bullet (monoclonal antibodies"



Fig. 2. Postulated mechanism underlying tumor antigen (TA)-specific T-cell-based immunotherapy and effect on target antigen expression. Localization of TA-specific
T cells at a tumor site appears to be necessary but not sufficient for tumor elimination [38,39]. If no response occurs, the interaction between T cell and tumor cell is
probably not sufficient (or sustained) to start or maintain an inflammatory process. If the treatment induces an adaptive response of a quality and/or intensity that exceeds
a certain ‘threshold’, then direct interaction of T cells with antigen-expressing (red circles) tumor cells leads to their destruction, as well as to the production of proinflammatory
and pro-apoptotic cytokines that induce secondary activation of adaptive and innate immune effectors capable of clearing tumor cells that have lost antigen
expression (white circles). If the tumor-cell destruction is not complete, the proliferation of remaining cells leads to recurrence. In those cases, the recurring tumors have
lost the surface expression of the epitope relevant to the vaccination [66,67]. Abbreviations: CR, complete response; PR, partial response; X, cells killed by the therapy.

Source:http://www.wistar.org/Herlyn/Pub%20PDFs/Marincola2003pdf.pdf

Tumors as elusive targets of
T-cell-based active immunotherapy

As you can see, the maxium Antibody level occurs on day 20. My Inflamed response occurred on day 15. This all fits together.






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

Melanoma and the “Magic Bullet” (Monoclonal Antibodies) first Draft Melanoma..Jim Breitfeller

Just to let you know I posted the first draft of the Melanoma and the “Magic Bullet” (Monoclonal Antibodies). on Melanoma Missionary In the Shared File Section. you can download it for 19.95 (Only kidding) it is Free for the taking. It is 33 pages long and may help you in your quest for the Yellow Brick Broad. Just to let you know it is only the first draft. Revisions are sure to come. I wanted to get it to the people that need it the most, the Melanoma Patients.

Preview:

So, where does Interluekin-2 (IL-2) come into play? According to Byung-Scok et al and recent reports, IL-2 is not needed for developmental CD4+ CD25+ Treg cells in the thymus but does play an important role in the maintenance and function in the peripheral.18 Peripheral is defines as secondary system outside the bone marrow and thymus. It entails the site of antigen, immune system interaction. IL-2 is required for the peripheral generation of Tregs based Abbas’s and colleagues research.19 IL-2 prevents the spontaneous apoptosis of the CD4+ CD25+ Treg cells. It has been reported that patients with multiple advance-stage tumors have elevated levels of Tregs within the tumor microenviroment.20 Interluekin-2 is the survival factor for CD4+ CD25+ Treg cells.21 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. By controlling the addition of the endogenous IL-2, one has a knob to turn and can lead to the control of the expansion of the Tregs. When you combined this control with the anti-CTLA-4 blockage, you can shift the balance of the immune response.

Now here is the catch. The maintenance and function of the CD8+ T-cells require CD4+ cells which secrete IL-2. So we don’t want to deplete the CD4+ cells, we want to control the expansion of the Tregs which are a subset of the CD4+ cells. It has been postulated by some researchers that the Anti-CTLA-4 blockage also suppresses the Treg function in a different mechanism. By using IL-2 as the rate limiting factor, we can suppress the CD4+ CD25+ Treg cell expansion by controlling the concentration and timing of the Inerluekin-2 at the tumor microenvironment.

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. As stated previously, 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, “An Inmmune Response Unrehearsed.”

On the other hand, prolong therapy with Il-2 can result in causing apoptotic death of the tumor- specific CD8+ T-cells.23
Clearly in a clinical setting, timing, dose, and exposure to these drugs play a major roll in the immunotherapy, and can have dramatic effects on the outcome. All it takes is that one magic bullet to start the immune reaction.


Take Care,

Jimmy B