Why did Bristol Myers Squibb make the compassionate Drug Dose of Ipilimunab 3.0 mg/Kg when the optimal is 10mg/Kg? Melanoma ..Jim Breitfeller

Based on a clinical trial NCT00289640, 10 mg/kg was the optimal dose.


According to Dr. Wolchok and investigating the dose of Anti-CTLA-4 blockage recently, the higher the dose the better the immune response. The best overall response rate was 11•1% (95% CI 4•9—20•7) for 10 mg/kg, 4•2% (0•9—11•7) for 3 mg/kg, and 0% (0•0—4•9) for 0•3 mg/kg (p=0•0015; trend test).


1 10mg/Kg 11.1% response rate
2 3mg/Kg 4.2 % response rate
3 0.3mg/Kg 0% response rate

This data was base on Ipilimumab
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70334-1/abstract

Ipilimumab monotherapy in patients with pretreated advanced melanoma


Study of Ipilimumab (MDX-010) Monotherapy in Patients With Previously Treated Unresectable Stage III or IV Melanoma
http://clinicaltrials.gov/ct2/show/NCT00289640

Study of Ipilimumab (MDX-010) Monotherapy in Patients With Previously Treated Unresectable Stage III or IV Melanoma


Compassionate Use Trial for Unresectable Melanoma With Ipilimumab

http://clinicaltrials.gov/ct2/show/NCT00495066?term=melanoma+ipilimumab&rank=9

Compassionate Use Trial for Unresectable Melanoma With Ipilimumab


Is this the Medical Scam of the Century? Where are the ethics?

Even in the Clinical trial it says: "Drug: Ipilimumab
Intravenous Solution, Intravenous, Ipilimumab 3 mg/kg, Ipilimumab - one dose every 3 wks for a total of 4 doses. Subjects who are eligible may receive another 4 doses given every 3 wks; Until disease progression, unacceptable toxicity or withdrawal of consent"



This trial is set up for failure and it is a well known fact that with this drug there is some progression before regression.





I believe Bristol Myer Squibb is doing a disservice to the Cancer Community especially the Melanoma Patients.





"What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life."

There is no commitment to patients with stage IV Melanoma.

They have dollars Signs in the eyes and don't give a cr%& about the patients.

This is what Big Pharma has become. (Greed)

Take Care,

Jimmy B

Tumors hide out from the immune system by mimicking lymph nodes Melanoma..Jim Breitfeller

Tumors hide out from the immune system by mimicking lymph nodes

Take Care,

Jimmy B

Tregs Rule without Anti-CTLA-4 Blockade Melanoma..Jim Breitfeller

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


Take Care,

Jimmy B

Déjà vu.. Blame it on the Tregs!! Melanoma..Jim Breitfeller

Déjà vu.. Blame it on the Tregs!!!!!!

As I reevaluate my theory, I have come full circle in my research and came across the research paper entitled:
The Role of Regulatory T Cells in Cancer
Tai-You Ha*
Department of Immunology, Chonbuk National University Medical School, Chonju, Chonbuk, Korea

The Role of Regulatory T Cells in Cancer






I postulate that the T regulatory cells may be the major stumbling block in the whole immunotherapy.
Recent studies have shown that CD4＋CD25high FoxP3＋ Treg cells are overrepresented in human metastatic lymph nodes with a 2-fold increased frequency
compared with both tumor-free lymph nodes and that advanced melanoma is associated with increased numbers of circulating Treg cells and Dendritic Cells (DCs) and suggested that melanoma induces immunosuppressive DCs and Treg cells in the systemic circulation of the patients . Vence et al also showed the presence of tumor antigen-specific CD4＋ Treg cells in the blood of patients with metastatic melanoma.

This means the host (you) may already have the correct antigen, but the tumor and microenvironment may be suppressing the immune response by secreting suppressive cytokines like TGF- beta , IL-10, and IL -6 and or proliferating the suppressive Tregs.

Nicholaou et al most recently showed in patients with melanoma that although strong antibody responses were mounted, the generation of delayed-type hypersensitivity response was significantly impaired and patients with advanced melanoma had a significantly higher proportion of circulating CD4＋ CD25＋FoxP3＋ Treg cells compared with those with minimal residual disease. So we now can blame the tolerance of our immune system to cancer on the T Regulatory Cells (Tregs).

It has been reported that the large number of different cell types that are claiming to be directly targeted by FoxP3＋ Treg cells are CD4＋, CD8＋ T cell, dendritic cells, B cells, marophages, osteoblasts, mast cells, NK cells, and NKT cells.


No wonder our immune system can’t raise an attack on the Melanoma. The tumor is like a castle in the middle ages. The castle (tumor) is surrounded by a moat the (suppressive cytokines) and the walls and towers are the Tregs. If you take out walls and tower, the castle becomes vulnerable.

These Tregs when activated, upregulate the CTLA-4, CD25 (IL-2), and other receptors. So if you control the function of the Tregs, you may be able to break the tolerance of the immune system. This can be done by blocking receptors on the Treg cells

It was also noted as the tumor burden increased, so did the Tregs in the peripheral which makes it harder to eradicate tumors in the advanced stage of Melanoma.



Wieczorek et al found that Treg cell numbers are significantly increased in the peripheral blood of patients with IL-2-treated melanoma. IL-2 stimulates CXCR4 expressed on the Tregs enables the Tregs to migrate CxCL12 in the tumor microenvironment increasing the Treg accumulation.

So we need to deplete, block and limit the expansion of the Tregs. We also want to limit the concentration of Interluekin-2 at the early stage of the CD4+ T-cell expansion. This can be done in a number of ways, but why not use an antibodies that can indirectly accomplish both tasks at once. By using anti-CTLA-4 blockage we keep the activation going, causing a free for all for the cytokine IL-2 that is secreted.

CD4+ T cells regulate immune responses by producing various cytokines upon antigen stimulation. Naive CD4+ T cells have limited cytokine responses and secrete only IL-2 before they differentiate into various effector cell types CD4+ T cells regulate immune responses by producing various cytokines upon antigen stimulation. Each cell type is competing for a limited amount of IL-2 secreted by a small subset of the T helper cells. Naive T cells stimulated with antigen in the presence of IL-4 differentiate into Th2 cells secreting IL-4, IL-5, IL-10, and IL-13, whereas IL-12 induces the differentiation of naive cells into Th1 cells secreting IL-2, IFN-γ, and lymphotoxin.



FROM:
Autoimmunity: IL-21: a new player in Th17-cell differentiation
Elissa K Deenick and Stuart G Tangye
WWW.Nature.com

Ribas and Restifo et al found that if you use Anti-CTLA-4 blockade the native T-cell is pushed towards the Th17 differentiation. This causes less interleukin-2 to be produced by the CD4+ T-cells causing a shortage of IL-2 in the microenvironment for the expanding T-cells thus limiting the differentiation to Tregs. It is well known that in the presence of TGF-beta and IL-2, the Native T-cell differentiates into T Regulatory Cells.

Also the activation and differentiation of Naïve CD8+ T cells require IL-2 provided by activated CD4+ T cells at the initial priming stage within 0–2.5 hours after stimulation. Thers is
critical IL-2 signal from CD4+ cells is mediated through the IL-2R (receptor) of Naïve CD8+ cells. This activation of IL-2 signaling advances the restriction point of the cell cycle, and thereby expedites the entry of antigen-stimulated Naïve CD8+ T-cell into the S phase of the cell cycle.

The cell cycle has four stages:

1. G1 phase when the cell increases in size and gets ready to replicate its DNA.
2. S phase when the cell synthesizes or copies its chromosomes
3. G2 phase in which the cell prepares to divide
4. M phase when mitosis occurs.

If no IL-2 is available to Naïve CD8+ T-cells, they never get a chance to expand and differentiate into Cytotoxic T Lymphocytes (CTLs) Killer T-cells.
Besides promoting cell proliferation, IL-2 stimulation increases the amount of IFNγ and granzyme B produced by CD8+ T cells.

Activation and Differentiation of (CTLs) Cytotoxic T Lymphocytes

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

For activation, the CTL-P needs at least three signals:

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

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

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

The Cytokine IL-2 came from the(CD4+) TH1 cells which means the CTL-P is IL-2 limited and can only be activated by the secreted IL-2 if there is any to be had or by introducing IL-2 through IL-2 therapy. Now you know the reasoning behind using the IL-2 therapy as the second part of the combinatorial Therapy. If there is not enough IL-2 in the host environment, you will only get partial expansion of the CTLs. It may not be enough to eradicate large bulky tumors.

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

Research suggests that the primary mode of the destruction of the tumors by CTL is by initiating death through the Fas-FasL pathway. Studies have shown that CTLs store Cytotoxic proteins in the form of granules in their cytoplasm.

These proteins belong to two categories:

1. Perforins: involved in pore formation
2. Granzymes: responsible for hydrolysis of the cellular products.

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

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

So now you know why Anti-CTLA-4 blockage and HD Interluekin-2 go hand and hand. Timing of the addition of IL-2 can make or break the immune response. And without suppressing the Tregs, your chances to mount an immune response may be slim at best. Your Immune System is a well Orchestrated system of events; we just need the Knowledge on how to harvest its potential on eradicating cancer.

The beginning of knowledge is the discovery of something we do not understand.
~Frank Hebert~
A critically acclaimed and commercially successful American science fiction author


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

Using personalized vaccines, researchers enlist the immune system to oust tumors.Melanoma..Jim Breitfeller

Using personalized vaccines, researchers enlist the immune system to oust tumors.

Getting Personal
BY KATY HUMAN
In 2003, Stephen Creel, a manager at a software company in Austin, Texas, suddenly started passing blood in his urine. He had just celebrated his 40th birthday with friends and his wife, who was pregnant with their daughter, and he was as fit as he’d been in years.

The diagnosis of kidney cancer—renal cell carcinoma—was “shocking,” Creel says.

His father-in-law, a cancer researcher, directed Creel to M.D. Anderson Cancer Center in Houston, almost 170 miles away, where oncologists were testing an experimental vaccine to treat kidney cancer.

They surgically removed patients’ tumors, sent samples away for processing, and then re-injected cancer-specific proteins back into the patient. They were trying to activate the patients’ own immune system cells, train them to recognize cancer as an invader, and fight it off.


Using personalized vaccines, researchers enlist the immune system to oust tumors


What if you could get your body to immunize yourself against Melanoma?
You would just need your immune system to recognize the tumor antigen.
You need the tumor to shed the right antigenic protein

It can and has been done. I am one of those cases.
Take a look at my jounery in the papers below.

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

Melanoma_Missionary


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

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

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

The paper that I am about to present to you is a culmination of research that was done base on my own experience as a stage IV Melanoma Patient. I wanted to know why my immune system responded and prove to myself and my doctors that it was not a statistical fluke. I dedicate this paper to all my fellow Melanoma Patients that lost their battle with the Beast, especially Bob Luker who fought so bravely but was unable to obtain Anti-CTLA-4 blockade due to the shortage proclaimed by Bristol Myer Squibb which halted compassionate drug use on 9-12-2008.

Most Melanoma tumors are accepted by the host’s immune system and progress even when they contain potentially antigenic proteins. This may be due to the tumor secreting immunosuppressive Cytokines like, TGF-Beta, IL-10, IL-4 and IL-6. TGF-β inhibits the proliferation and functional differentiation of T lymphocytes. TGF- Beta accelerates the expression of CTLA-4 by stimulated CD4+CD25– T cells. TGF- Beta requires CTLA-4 early after T Cell Activation to induce FoxP3 and generates adaptive CD4+CD25+ (Treg) Regulatory Cells. The tumor cells secrete TGF-Beta.

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




Take Care,

Jimmy B

Off thr beaten path, Lost a dear relative in a Motorcycle accident..Melanoma..Jim Breitfeller

For all you out there, Life is so fragile.

"Live like there is no tomorrow, because you never know what tomorrow will bring."

If I leave here tomorrow
Would you still remember me?
For I must be traveling on, now
'Cause there's too many places
I've got to see

But, if I stayed here with you, girl
Things just couldn't be the same
'Cause I'm as free as a bird now
And this bird, you'll can not change
Oh, oh, oh, oh, oh

And the bird you cannot change
And this bird you cannot change
Lord knows, I can?t change
Bye, bye, baby it's been a sweet love

Yeah, yeah
Though this feeling I can't change
But please don't take it so badly
'Cause the Lord knows
I'm to blame

But, if I stayed here with you girl
Things just couldn't be the same
'Cause I'm as free as a bird now
And this bird, you'll can not change
Oh, oh, oh, oh, oh

And this bird you cannot change
And this bird you cannot change
Lord knows, I can't change
Lord help me, I can't change
Lord I can't change

Won't you fly high, free bird, yeah?




Patti just did that.

Patti will be dearly missed.

4 motorcyclists killed in crash identified

http://tampabay.com
The Associated Press

BUSHNELL, Fla. -- Authorities have identified the names of the four motorcyclists killed following a collision on a central Florida road.

The Florida Highway Patrol says the victims were killed Saturday night in Bushnell after leaving a gathering with friends when their bikes were struck head-on by a truck trying to pass another vehicle.

Killed were 54-year-old William Barker; his passenger, 55-year-old Patrice Poole; 55-year-old John Holmes; and his passenger, 52-year-old Patricia Beihayn (Patti Breitfeller).

Authorities say 45-year-old Paul Sermons didn't realize how close two motorcycles in the other lane were and wasn't able to slow down before the collision.

The drivers and passengers of the motorcycles were all ejected in the crash.

Sermons received minor injuries in the crash.


Information from: St. Petersburg Times, http://tampabay.com


Read more: http://www.miamiherald.com/2010/03/16/1531486/4-motorcyclists-killed-in-crash.html#ixzz0iLgsZWNi


Take Care,

Jimmy B

New Options in Melanoma Therapy Dr John Kirkwood Feb 2010..Jim Breitfeller

Take Care,

Jimmy B

What You Don’t Know Might Kill You..Melanoma ..Jim Breitfeller

What You Don’t Know Might Kill You

"He made this his cause after his wife, diagnosed with advanced breast cancer a decade ago, had to fly from their home in Wisconsin once a month to be treated at NCI. She participated in a clinical trial there, surviving months longer than expected. When your husband is one of the nation's top oncologists, you know where to go. As for the other 1,490,000 people who are diagnosed with cancer this year, good luck."


The right doctors can make all the difference when it comes to treating cancer. So why don't we know who they are?

What You Don’t Know Might Kill You


So for Melanoma Here is the short list.

Melanoma Care Centers in the US



Take Care,

Jimmy B

Driving in the Melanoma Landscape.. Jim Breitfeller

Driving in the melanoma landscape
Viewpoint
Dr. Meenhard Herlyn
The Wistar Institute, Philadelphia, PA, USA

Abstract: The melanoma landscape is rapidly evolving. The
melanoma oncologists have now the first successful targets for
therapy that have a genetic base – albeit in rare forms of the
malignancy. Once melanoma becomes part of the Cancer Genome
Atlas consortium, a comprehensive map of genetic changes will be
established to point the field to true drivers of the disease that
will become new targets for therapy. The same abnormalities will
also serve as biomarkers for diagnosis, prognosis and therapy
follow-up. Melanomas as a group are heterogenous as are tumor
cells within one lesion. New strategies will move towards
individualized therapies and combination therapies to target all
cells within a tumor.

Driving in the melanoma landscape


Please take time to read this viewpoint from a world renowned Researcher in Cancer





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


Melanoma and The Magic Bullet (Monoclonal Antibodies)




Take Care,

Jimmy B

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

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


Dear Dr. Sigal:

I want to thank you for responding to my emails over the last few months. I know I can be candid and straight to the point sometimes. By reopening the compassionate Drug Use (ipilimumab) you and your company gave the Melanoma Patients “The Last Chance of HOPE”. You don’t know how much this means to us. If we haven’t passed the “Lethal Tumor Burden” we still have a chance of survival. I believe you have done your company justice and showed your compassion. My faith in the Company’s Ethics have been restored.

Now we need to prove to the world that this drug may be one of the most important discoveries in the last twenty years of Cancer. By taking the “Brakes off the Immune System” we can harness our own immune system to battle cancer. Granted we may have to use the drug in combinatorial therapy to rid the host of the cancer once and for all. I hope you and your company can collaborate together with all the major players in this exciting field of Oncology. See it took millions of years for our immune system to evolve, so why do we think that one drug can do it all. We need to approach the Beast arm to arm, to block all the pathways so it can’t escape. This can only be done by using one’s own immune system.

Can you imagine working out a protocol that will vaccinate the patient with the patients own tumor–specific antigen? And Ipilimumab (Anti-CTLA-4 Blockade) is at the center of this
revolutionary therapy/protocol. Please if you get a chance, listen to some of the lectures and symposiums from the like of Dr. James Allison, Dr. Jedd Wolchok, Dr. Antonio Ribas, Dr. Jeffery Weber,Dr. Keith Flaherty and others. You will be amazed at their accomplishments in the clinical setting. But they need more. They need access to the entire drug arsenal that is available across companies. We now know that timing and dose concentration plays a major roll in setting up an immune response. There are feedback loops. It is like dominos. You have this elaborate step-up. It may take weeks to build. Once you set it in motion, the chips begin to fall. There are different pathways, cytokines, T-cells, receptors, etc that need to be taken into account get the right immune response. This immune response can only be generated if you have all the keys to unlock the response. We need yours and other Pharmaceuticals to work together for the good of the cancer patients. We need to take down all the red tape which also includes the FDA.

“Our Life depends on it.”




Thanks again.
Sincerely,
Jim Breitfeller

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

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





Jim,

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

Elliott


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

Melanoma and The Magic Bullet (Monoclonal Antibodies)




Take Care,

Jimmy B

Expanded access is currently available for this treatment! Melanoma..Jim Breitfeller

Source:http://clinicaltrials.gov/ct2/show/NCT00495066

Expanded access is currently available for this treatment Ipilimumab


Melanoma_Missionary


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

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

Melanoma and The Magic Bullet (Monoclonal Antibodies)




Take Care,

Jimmy B

Future Directions in Targeted Therapy for Melanoma..Jim Breitfeller

Future Directions in Targeted Therapy for Melanoma

“Our improved understanding of the molecular pathways that underlie the progression of melanoma has revealed numerous potential therapeutic approaches. We now face the challenge of developing targeted therapies directed at signaling pathways that are activated through mutations. Single-agent therapy is unlikely to be markedly successful,so there is also a pressing need to evaluate combination therapies, both with multiple targeted therapies and with targeted therapies plus conventional chemotherapeutic agents. It is hoped that these approaches will result in effective treatment options for patients with metastatic melanoma.”

~Dr. Keith T. Flaherty~


The Complexity of the T cell

In the midst of many promising discoveries, it became apparent to Dr. Allison and other researchers working in the field that stimulation of T cell response was more complicated than originally thought. As Dr. Allison and others discovered, first the T cell uses a structure called the antigen receptor to recognize a foreign antigen in the system (created by infecting viruses or bacteria, or new antigens found in tumor cells). Using an automobile as an analogy, Dr. Allison likens this step to turning the key in the car's ignition. "The car is running, but it's not going anywhere."

Recognition is not enough. Dr. Allison explains: "A second signal is also required, which, in the car analogy, would be the foot on the gas pedal." This second signal occurs when a particular family of molecules called the B7 molecule engages a molecule known as CD28 found on the surface of the T cell. Only these molecules are capable of initiating T cell response.

The final part of the car analogy is the immune system's brake -- an immune-regulating molecule, whose function was discovered by Dr. Allison's lab, known as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 inhibits activated T cells in the immune system, preventing them from attacking the body's own tissues

It is now well accepted that recognition of specific antigen by the TCR is not sufficient for activation but that a second antigen nonspecific "co-stimulatory" signal is required. We have demonstrated that this second signal is provided the co-stimulatory receptor CD28 upon recognition of its counter-receptors, members of the B7 family, on the antigen-presenting cell. CD28 engagement is required under most situations for IL-2 production and proliferation. The lack of a CD28-mediated co-stimulatory signal upon TCR engagement can result in the induction of a long-lived state of nonresponsiveness.

We have recently found that co-stimulation is more complex than previously thought. CTLA-4, a homolog of CD28, also binds members of the B7 family, and binds them with affinities much higher than CD28. A wealth of data accumulated in the past few years show that CTLA-4 is an important downregulator of T cell responses. We have proposed that CTLA-4 plays a critical role in both the initiation and termination of T cell responses. According to this view, T cell activation is a dynamic process that is determined by the strength of the TCR signal; the strength of co-stimulation provided by CD28; and the magnitude of inhibitory signals generated by CTLA-4.

We have also demonstrated that CTLA-4 blockade can be used in combination with other methods of immunopotentiation or even conventional chemotherapy to obtain rejection of resistant tumors. We are currently examining the cellular and molecular mechanisms of the anti-tumor effect. The strategies we have developed in the mouse are currently in clinical trials for evaluation of effectiveness in treatment of prostate cancer and melanoma

Source: Sloan-Kettering Institute

"I believe that we are on the verge of bringing the manipulation of immune responses into the mainstream of cancer therapy," Dr. Allison said. "Recent work in cancer biology has shown that the genetic instability that is inherent in cancer results in a large number of mutations in proteins that create new antigens that the body has never seen before and ought to be readily recognized as foreign by the immune system. If we can kill some tumor cells, either as a result of a vaccine or treatment with more-conventional therapies, using agents such as anti-CTLA-4 ought to result in induction of potent immunity to these new targets. Thus, I believe that it is not unreasonable to think of many of the new targeted therapies as immunosupportive, and to use them in conjunction with the new approaches to enhancing immune responses."

~Dr. James Allison~

We are on the Verge of Harnessing the Immune System to recognize Melanoma cells as foreign. How this plays out will depend on if the Pharmaceutical companies like Bristol-Myer Squibb, Novartis, Pfizer, Hoffman La Roche, Plexikkon and other come together as one, to fight this Monster of a disease. Time will only tell. We owe it to the Patients.






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~

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

Melanoma and The Magic Bullet (Monoclonal Antibodies)

Challenges and Opportunities Ahead..Melanoma Therapy ..Jim Breitfeller

"A dynamic picture is emerging in which the immune system is far from quiescent in cancer, and tumor cells elaborate a host of countermeasures to evade immune destruction. In essence, these are two systems which co-evolve over time. Clinical outcome is ultimately a balance between the proliferation of tumor cells and the immune response which attempts to control these cells. Various treatments may perturb these two systems in different ways - in good clinical outcomes, the immune response ultimately dominates, while in poor outcomes, tumor cells dominate.

It is becoming clear that the challenge in tumor immunotherapy lies not only in lack of tumor recognition, but also ineffectivity of the immune response that develops. While efforts to elicit tumor-specific T cells directly in patients via vaccination may overcome potential mechanisms of immune evasion by tumors cells, current immunotherapeutic strategies do not address their potential immunomodulatory mechanisms.

Understanding the molecular mechanisms which underlie T cell dysfunction in cancer will be important to devise novel adjunct strategies to enhance or modulate T cell responses after tumor-specific T cells have been elicited. It will likely take a multi-faceted approach acting at several steps along the T cell activation and effector activity pathway to finally achieve success in cancer immunotherapy."


The Laboratory of Peter P. Lee, MD at Stanford University

This multi-faceted approach acting at several steps along the T cell activation and effector activity pathway is what I call Combinatorial Therapy.

We first start at obtaining the Antigen to be presented on the Antigen Presenting Cell. Then once we think we got it, we need to proceed to the Activation step. Ipilimumab (Anti-CTLA-4 Blockade) helps to keep the activation in the on position. It also has a dual role, in keep the Treg's surpressive function out of play in the Tumor 's microenvirioment.
Interleukin -2 is the final step to complete response. It is the growth factor for the CTL's, which help maintain functionality and survival of the Cytotoxic T Lymphocytes (CTL's).






Take Care,

Jimmy B

How Ipilimumab could work for You!! Melanoma.Jim Breitfeller

Pictures are from Bristol-Myer Squibb.

"If the timeline Fits, You must build it"

A Clinical Trial with this Protcol Design.


Take Care,

Jimmy B

Bristol-Myer Squibb says it will seek FDA approval for ipilimumab as a second-line treatment in advanced melanoma in 2010.Melanoma..Jim Breitfeller

Bristol-Myer Squibb says it will seek FDA approval for ipilimumab as a second-line treatment in advanced melanoma in 2010.

"Phase 3 top-line results are due from a study of ipilimumab in patients with previously untreated metastatic melanoma taking a combination of ipilimumab plus the chemotherapy dacarbazine or dacarbazine plus placebo. Concurrent with a business update to analysts and investors on Mar. 4, BMS says it will seek U.S. regulatory approval for ipilimumab as a second-line treatment in advanced melanoma in 2010, and will move the drug into Phase 3 trials in non-small cell lung cancer based on Phase 2 study data, which it would present at a major medical meeting later in 2010. The company did not provide any additional details on the data."

Source:










Bristol-Myer Squibb's Ipilimumab Can't Cure Cancer alone, It will need to be done with Combinatorial Therapy.









Take Care,

Jimmy B

Now that Ipilimumab is coming availble, please consider combinatorial therapy..Melanoma..Jim Breitfeller

Now that Ipilimumab is coming availble, please consider combinatorial therapy



Melanoma and The Magic Bullet (Monoclonal Antibodies)





Dr. James Allison of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center in New York, New York, described his laboratory’s latest research into the mechanisms of immune checkpoint blockade in the treatment of cancer, and showed data from mouse and human studies that support the further investigation of immune checkpoint blockade therapy alone and in combination with other anti-cancer therapies.

Source:http://www.cancerresearch.org/Programs.aspx?id=2412


The mechanisms of immune checkpoint blockade in the treatment of cancer











Take Care,

Jimmy B

There is No Magic Bullet to Cure Melanoma, And We Must Develop Multimodality Strategies..Melanoma..Jim Breitfeller

Expert opinion
“The research efforts directed towards the development of novel therapies for patients with metastatic melanoma have been intense despite disappointing clinical outcomes. It is clear that monotherapy for metastatic melanoma will not be successful, with every study to date yielding minimal clinical outcomes
data. Therefore, we must realize that there is no magic bullet to cure melanoma, and we must develop multimodality strategies to enhance the immune response to melanoma from different angles. This will require an unprecedented collaborative effort by many in order to overcome the historical competition between large pharmaceutical companies striving for ‘total cure’ with their drug.”

~ Dr.Adam I Riker~

We should realize that the future of drug development and design will depend heavily on the recent trend towards molecular medicine, and in particular, gene profiling efforts using gene microarray analysis. We are entering an entire new field of research dedicated to the molecular basis of cancer. Such research has the greatest potential to impact the way we treat patients with melanoma, focusing results on the prognostic significance of particular genes from a melanoma patient and basing clinical decisions as to whether such patients will (or will not) respond to a particular agent. The development of molecular signatures using gene microarray analysis has come to the forefront of existing research efforts identifying patients who may have an aggressive (versus indolent) form of melanoma and those patients with particular prognostic gene
signatures that may predict the response to forms of immunotherapy. The identification of such gene signatures has had important implications in the development of targeted immunotherapies for patients with metastatic disease. Thus, we must focus our efforts towards an improved understanding of the molecular and immunologic events involved in melanoma development and progression. We should also re-evaluate our present approach to immunotherapy and trial design, with many past trials failing to show clinical efficacy because of a lack of appropriate preclinical data that provide the essential rationale to perform such studies.

Source: http://www.southalabama.edu/mci/spf90/riker2.pdf

Immunotherapy of melanoma: a critical review of current concepts and future strategies








Take Care,

Jimmy B