Thursday, May 6, 2010

The Proof is in the Science..Is Bristol Myer Squibb missing the Boat? Melanoma..Jim Breitfeller

The Proof is in the Science..Is Bristol Myer Squibb missing the Boat?

So why is Bristol Myer Squibb going to commercialize Ipilimumab at 3mg/Kg instead of 10 mg/kg?

Could it be possible that BMS is looking to add a Maintenance phase to the therapy? Or is it because of the high 3-4 adverse effects at the higher dosage?

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). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0•3 mg/kg, respectively; the most common grade 3—4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0•3 mg/kg group) and diarrhea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0•3 mg/kg group).

Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg.

Bristol-Myers Squibb


Elliott Sigal said in the Bristol-Myers Squibb Q1 2010 Earnings Call “We do plan to commercialize the 3-milligram dose and the indication that I mentioned.”

So with that, there may be a problem with dose being to low. Based on the information that I have obtained, 3mg/ Kg may be to low to block all the CTLA-4/B-7 receptors on the T-cells. Cells known to express CTLA-4 include activated CD4+ and CD8+ T cells, and B cells.

So if you don’t activate the T-cells, the CTLA-4 receptor is not up-regulated and the Ipilimumab is not tied up. That is why we see excess Ipilimumab at low concentrations.
What we want to look at is the maximum delta (change between) time intervals. If the T-cells are activated, then the delta would be greater than the half-life of the Ipilimumab.

It has been noted that we need at least 10ug/ml in the serum Ipilimumab to block all the CTLA-4 receptors. With that in mind we need to take into account the drug’s half life and we must also take into account the T-cells expansion over time of the Activation.

So we need to start out with enough Ipilimumab to last through the T-cell expansion and activation.

With that in mind, we should start at 0 to 33 days. That is the time the CD4+ T-cells need to reach maximum propagation.

We should also look at the interval of 33 to 64 days. That is the time frame when the CD8+ T-cells are at their maximum expansion.

The 0.1 and 0.33 mg/kg are to low to complete the 33 day interval. This means those two points are substrate limited. (Not enough Ipilimumab)

The mean ± SD MDX-CTLA4-01 terminal elimination half-life was 299.4 ± 126.9 h (12.475 days).

12.5+/-5.3 days is the elimination Half Life of the Ipilimumab


Adaptive from A. Bashey

At 1536 hours or 64 days at 3mg/kg, there is still some anti-CTLA-4 in the blood system, but it is far below 10 ug/ml level
According to the research, you need at least 10 ug/ml to saturate all the CTLA-4 receptors in host’s body. Base on the work research done by Bashey et al, 3 mg/kg dose of Ipilimumab will only get you to about 4ug/ml in the host’s serum. 3mg/kg of Ipilimumab falls short of blocking all the CTLA-4 receptors. This is why I believe that this is one of the reasons for such a low response rate.

By back calculating from day 64, and using the half-life of 12.5 days, one would need at least 9.6 mg/kg to block all the CTLA-4/B-7 pairs. But does this take into the account of the expanding and activated T-cells?

Dr. Jedd Wolchok did a dose concentration experiment and determined that 10mg/kg of Ipilimumab gave the best response rates.

But the new dose concentration 10 to 15 mg/kg used, so there is 3 to 4 times amount of Anti-CTLA-4 in the serum which means at 64 days into the activation of T-cells, there should be enough anti-CTLA-4 antibodies to block the newly upregulated CTLA-4 receptors of the expanded CD4 and CD8 T-cells and Tregs, not to mention the B-cells.

Elliott Sigal
“Yes, Jami. Let me address the comment. I would not call 020 not pivotal. It wasn't pivotal in our thinking years ago. And as a result of conversations with health authorities, and this is why we do this, we decide what is an appropriate indication on file for and do we have data to enable a review. Of Phase III study, that's survival with ipilimumab that does compare against an experimental vaccine in previously treated patients. We consider pivotal to the indication of metastatic melanoma in previously treated patients, where there is no standard of care and therefore we feel it's appropriate standard of care is often experimental regimen to compare with the well-characterized experimental treatment and we chose the vaccine. We have an adequate study to check the contribution of ipi alone as well as ipi in combination with the vaccine. We do not to commercialize the vaccine. We do plan to commercialize the 3-milligram dose and the indication that I mentioned. The old 24 first-line study is a different patient population and a different regiments. And when that data becomes available, we hope to provide enough information from that study to talk about an expanded indication for the drug.”


Conclusion: 3mg/kg of Ipilimumab is to low in my opinion to produce the response rates that the patients are looking for. We desperately need the dose range between 10 to 15 mg/kg to get more complete responses. We need to suppress the Treg function and keep the T-cells activated longer.

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

Take Care,

Jimmy B



  1. i put a comment on that was supporting bms and their going for fda approval by bringing their stats to the asco meeting june 4-8 2010 and then sending the stats to the fda by august 2010 and getting approval, hopefully by dec 2010, for ipi with or without vaccine therapy. once ipi is approved by the fda, it then will be handled by one's own personal oncologist and no longer be in the clinical trial and monitored by what is the big deal here?

  2. ipilimumab is an excellent drug alone, as well, and bms also has some really good stats from trials of ipi alone, and with vaccine therapy. some people cannot tolerate il2, and that is only one other option. side effects of il2 can be deadly. mdx010-ipilimumab's side effects are usually fairly manageable, and they know how to deal with them (the doctors). so, getting ipi for melanoma survivors who are in late stage, and getting it alone, even if it isnt the 10% right now, is great!!!!get it flowing and helping people. it is proven to be one of the best drugs for metastatic melanoma...this is some hope for the face of this beast.


Greetings to One and All

This Blog is dedicated My Brother Kenny B. who passed away in the late 1970's with Cancer before the Internet.

It was he, who showed me How to live and give back. He was wise beyond his years.

Kenny B

Jimmy and Dee

Carepage: Jimmybreitfeller
Jimmy Breitfeller

My Profile as of 2009

My photo
Last July (2005)I was riding my bicycle to work at the Eastman Kodak Research Labs about 3 miles from home. I was wearing a knapsack to carry my things to and from the labs. I started noticing an ache on my back. So I decide to go to the dermatologist. To make the long story short, it was cancer. I knew from my research that I would be needing adjuvant therapy. So I started communicating with Sloan Kettering, University of Pittsburgh Cancer Center, and a couple of others including the Wilmot Cancer Center at Strong. I realized that by telling my story, I might help someone else out there in a similar situation. So to all who are linked by diagnosis or by relation to someone with melanoma, I wish you well. Stay positive, read as much as you can (information helps to eliminate the fear associated with the unknown), and live for today, as no one can predict what tomorrow may bring. Jimmy B. posted 12/15/08


The information contained within this Blog is not meant to replace the examination or advice of your Oncologist or Medical Team. The educational material that is covered here or Linked to, does not cover every detail of each disorder discussed.

Only your physician/Oncologist can make medical decisions and treatment plans that are appropriate for you. But, An Educated Consumer is a Smart consumer.

As Dr. Casey Culberson Said:

"The BEST melanoma patient is an ACTIVE PARTICIPANT in his or her treatment

Melanoma and the “Magic Bullet” (Monoclonal Antibodies)

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.


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,

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..

Melanoma And The Magic Bullet (Monoclonal Antibodies)

Public Service Announcement

A call for Melanoma Patients by Dr. Steven A Rosenberg

"We continue to see a high rate of clinical responses in our cell transfer immunotherapy treatments for patients with metastatic melanoma", Dr. Rosenberg said.

"We are actively seeking patients for these trials and any note of that on a patient-directed web site would be appreciated."

If you would like to apply for his trials, here is the website and information.

Dr. Rosenberg's information

Dr. Rosenberg's Clinical Trials

For the Warriors

The Melanoma Research Alliance has partnered with Bruce Springsteen, the E Street Band, and the Federici family to alleviate suffering and death from melanoma. Please view Bruce Springsteen’s public service announcement inspired by Danny Federici. Danny was the E Street Band’s organist and keyboard player. He died on April 17, 2008 at Memorial Sloan-Kettering Cancer Center in New York City after a three year battle with melanoma.

Source Fastcures blog

Join the Relay for Life!!!


Dear Family and Friends,

I’ve decided to take a stand and fight back against cancer by participating in the American Cancer Society Relay For Life® event right here in my community! Please support me in this important cause by making a secure, tax-deductible donation online using the link below.

To donate on line now, click here to visit my personal page.
Jimmy B AKA Melanoma_Missionary

Relay For Life® is a life-changing event that brings together more than 3.5 million people worldwide to:

CELEBRATE the lives of those who have battled cancer. The strength of survivors inspires others to continue to fight.

REMEMBER loved ones lost to the disease. At Relay, people who have walked alongside people battling cancer can grieve and find healing.

FIGHT BACK. We Relay because we have been touched by cancer and desperately want to put an end to the disease.

Whatever you can give will help - it all adds up! I greatly appreciate your support and will keep you posted on my progress.

Keep the Fire Burning!!!



Jimmy Breitfeller
Turn off Music before you "Click to Play"
Signs of Melanoma Carcinoma Skin Cancer

How Skin Cancer Develops by " : Dermatology"

Call for Patients with Unresectable Liver Metastases Due to Melanoma

Delcath Systems Granted Orphan-Drug Designations for Cutaneous and Ocular Melanoma

Delcath is actively enrolling patients in a Phase III clinical trial testing its proprietary drug delivery system, known as Percutaneous Hepatic Perfusion (“PHP”), with melphalan for the treatment of ocular and cutaneous melanoma metastatic to the liver.

This NCI-led trial is enrolling patients at leading cancer centers throughout the United States. Commenting on these orphan-drug designations, Richard L. Taney, President and CEO of Delcath, stated, “These favorable designations are important steps in our efforts to secure Delcath’s commercial position upon conclusion of our pivotal Phase III trial for metastatic melanoma. We remain steadfast in our commitment to become the leader in the regional treatment of liver cancers and we continue to enroll patients in this study, and advance our technology and the promise that it offers to patients with these deadly forms of melanoma and other cancers of the liver, all with limited treatment options.”

Orphan drug designation, when granted by the FDA’s Office of Orphan Products Development, allows for up to seven years of market exclusivity upon FDA approval, as well as clinical study incentives, study design assistance, waivers of certain FDA user fees, and potential tax credits.

Current Trial Centers

Phase I Study of Hepatic Arterial Melphalan Infusion and Hepatic Venous Hemofiltration Using
Percutaneously Placed Catheters in Patients With Unresectable Hepatic Malignancies

James F. Pingpank, Jr., MD, FACS
Associate Professor of Surgery
Division of Surgical Oncology
Suite 406, UPMC Cancer Pavillion
5150 Centre Avenue
Pittsburgh, PA 15232
412-692-2852 (Office)
412-692-2520 (Fax)

Blog Archive

Call For Melanoma Patients!!!!

Call For Melanoma Patients!!!!

Dr. Rosenberg Has a New Clinical Trial.

Our latest treatment has a 72% objective response rate with 36% complete responses.

We are currently recruiting patients for our latest trial.

Is there some way to post this “Call for Patients” on the web site?

Steve Rosenberg

Dr. Rosenberg's Clinical Trials

(For a copy of the research paper.. see My Shared files)

The news headlines shown above for Melanoma / Skin Cancer are provided courtesy of Medical News Today.