Wednesday, July 4, 2012

Interview With Michael B. Atkins, MD Immunotherapies in Melanoma.Jim Breitfeller

Interview With Michael B. Atkins, MD Immunotherapies in Melanoma: Taking Stock
 Alice Goodman, MA; Michael B. Atkins, MD

 Posted: 07/02/2012

 Editor's Note: Immunotherapy is the only treatment that can produce durable tumor regression in patients with metastatic melanoma. With novel molecularly targeted agents also being developed for metastatic melanoma, the hope is to learn how to combine and sequence these therapies and improve survival for patients with this once universally fatal disease. At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO®), Dr. Michael B. Atkins, Deputy Director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, chaired an educational session on immunotherapy in advanced melanoma.

 Medscape caught up with Dr. Atkins to ask him to put into perspective the emerging data on immunotherapy and what questions still need to be answered.

IL-2 Opens the Door Medscape:
 What was the first immunotherapy to show an effect in metastatic melanoma?

Dr. Atkins: High-dose interleukin (IL)-2 received US Food and Drug Administration (FDA) approval for the treatment of patients with metastatic melanoma in 1998. A number of durable responses were observed and 11% of patients were alive at 5 years.[1] More recent studies have shown that patients with elevated lactate dehydrogenase (LDH) levels are much less likely to respond to IL-2, with about a 6% response rate in patients with elevated LDH (all partial responses) and about 21% in those with normal LDH levels.[2] Analysis of molecular profiles shows that a significantly larger proportion of patients with BRAF- and NRAS-mutated tumors respond to IL-2 than those who do not have these mutations. Also, we now have information suggesting that tumors with an inflamed phenotype and immune infiltrates have a 2- to 3-fold improved chance of response relative to those with a noninflamed gene expression pattern.

Michael B. Atkins, MD
Medscape: Has IL-2 been combined with other immunotherapies?

Dr. Atkins:
 IL-2 has been combined with vaccine therapy. Results of a randomized trial found that the combination of IL-2 plus vaccine produced response rates of 22.1% compared with 9.7% with IL-2 alone, and a trend was observed toward improved overall survival.[3] Median survival was 17.6 months with the combination of IL-2 plus vaccine vs 12.8 months with IL-2 alone. Very few relapses were seen beyond 2 years in responding patients, a hallmark of effective immunotherapy. However, lower-than-expected response rates were reported for the IL-2-alone group, calling into question how much of an advance this treatment is. Some questions remain: Is this a proof of concept that the immune response can be focused by a vaccine? Will the findings be relevant with novel immunotherapies? Ipilimumab: A Check-Plus for a Checkpoint Inhibitor Medscape: More recently, ipilimumab, a different type of immunotherapy, was approved by the FDA for the treatment of metastatic melanoma. This drug is referred to as the first checkpoint inhibitor, meaning that it interferes with an important downregulatory property of the immune response.

How does this drug work, and what kinds of outcomes does it achieve?

Dr Atkins: The monoclonal antibody ipilimumab blocks CTLA-4, which serves as a coregulatory protein that shuts off the immune response when it binds to a protein on antigen-presenting cells. Blocking CTLA-4 restores immunity. Ipilimumab has been evaluated in a variety of clinical trials. It is administered intravenously once every 3 weeks for 4 doses on an outpatient basis. Its side effects result primarily from induction of immune reactions against normal tissues, but in general, it produces fewer inflammatory systems (eg, fever, chills, hypotension) than those associated with high-dose IL-2. A recent trial compared ipilimumab plus gp100 vaccine vs ipilimumab alone vs the vaccine alone.[4] In both ipilimumab-containing arms, survival was prolonged. One-year survival was 46%, 44%, and 26% for the 3 arms, respectively. Two-year survival was 22%, 24%, and 14%. Few deaths occurred in the ipilimumab-treated patients after 30 months.

Medscape: What about the safety profile of ipilimumab and patient selection?

Dr Atkins:
The toxicities of ipilimumab are related to activation of the immune system and include colitis, dermatitis, endocrine effects, and hepatitis. In clinical trials, all subgroups benefitted from ipilimumab, with the possible exception of patients with elevated LDH. One feature of ipilimumab is apparent disease progression early in the course of treatment followed by a major response, so we have learned that the effect of treatment is not seen immediately. Pooled data from clinical trials suggest that about 25% of patients with metastatic melanoma have long-term benefit from ipilimumab therapy, and the benefit might be greater with a higher dose of the drug. Also, there is a potential role for maintenance therapy with this agent.

Medscape: Has ipilimumab been studied in combination therapy?

Dr Atkins:
A study was conducted in previously untreated patients with metastatic melanoma in which the patients were randomly assigned to dacarbazine alone or dacarbazine plus ipilimumab.[5] Some experts expected better results than were achieved in this first-line setting, and it is possible that dacarbazine may have compromised outcomes.

Medscape: What are the take-home messages about ipilimumab for metastatic melanoma?

Dr. Atkins:
Ipilimumab enables an immune response and antitumor responses in some individuals. This agent is powerful enough to work in the central nervous system and overcome concurrent immunosuppression. The response to ipilimumab may be associated with autoimmunity. Activity of the drug is seen in patients previously treated with IL-2. This drug is an option for most patients with advanced melanoma. Optimal timing of therapy and severe autoimmune toxicities should be considered. We don't know the answers to all of the questions about how to use ipilimumab. Should it be combined with dacarbazine? Should it be used as first-line or second-line treatment? What is the optimal dose and schedule? Does it have a role in maintenance therapy? What is its role in the adjuvant setting? What combinations should be studied? Some possible combination partners are bevacizumab, GM-CSF [granulocyte-macrophage colony-stimulating factor], high-dose IL-2, and the novel PD-1 antibody. PD-1 Inhibitor: New Kid on the Block Medscape: At the 2012 annual meeting of ASCO®, we heard exciting preliminary reports about a second checkpoint inhibitor called MDX-1106, a PD-1 antibody.

 How does this immunotherapy work, and what are preliminary observations?

 Dr. Atkins:
On activated T-cells, PD-1 serves as the receptor for PD-L1, which is expressed on tumor cells. When PD-L1 binds to PD-1 inside the tumor microenvironment, it paralyzes T-cell immune function. Blocking the interaction between PD-L1 and PD-1 with an antibody provides a specific way to activate the immune system within the tumor microenvironment. It is hypothesized that this would provide a less toxic and more potent means of activating the immune system. Several presentations at ASCO® on this novel immunotherapy showed exciting preliminary results. A large phase 1 study evaluated MDX-1106 given every 2 weeks for up to 2 years in patients with melanoma, renal, and non-small cell lung cancer.[6] Durable responses were seen in all 3 malignancies. In the melanoma patients, about half had tumor shrinkage and some responses were quite significant. This novel therapy will move forward in clinical development for patients with melanoma, either as a single agent or in combination. A number of PD-1 and PDL-1 blockers are under development. Which Patients Are Right for Immunotherapy?

Medscape: How do you select patients for treatment with immunotherapy?

 Dr Atkins: Patients with metastatic melanoma are not all the same. There are 2 basic phenotypes: noninflamed and inflamed. Data suggest that the second phenotype is associated with a better prognosis; that is, the greater the percentage of immune cells within a tumor, particularly CD8+ T cells, the better the prognosis. As mentioned previously, patients with tumors expressing an immune signature are more likely to respond and to exhibit a longer progression-free survival than those with tumors that do not have this signature. Studies suggest that PDL-1 expression appears to be associated with benefit, because patients without PD-L1 expression were less likely to respond to PD-1 antibody.[6-8] Sequencing: Which Therapy, and When? Medscape: What is the current thinking on sequencing of therapies? Dr Atkins: In addition to immunotherapies, several new targeted therapies are on the horizon. Vemurafenib, which targets tumor containing a BRAF V600E mutation, is approved for the treatment of patients with metastatic melanoma, and other BRAF and MEK inhibitors are being studied. These therapies may be able to be used in combination with immune therapies to improve outcomes. Most patients would like a chance to be cured. Immune therapies are the only curative therapies for advanced melanomas. Thus, if patients can receive an immune therapy, it may be better to give it first. For BRAF wild-type tumors (those without the BRAF V600E mutation) and even for the BRAF-mutated tumors, it might make sense to give patients an immunotherapy first to try to produce long-term benefit and reserve the use of a BRAF inhibitor for those patients who don't respond to immunotherapy. Data suggest that giving an immunotherapy first does not reduce the ability to respond to a BRAF inhibitor. On the other hand, patients who progress on vemurafenib do not appear to respond to ipilimumab. In fact, in a small study of 32 patients whose disease progresses on vemurafenib, 50% were dead within 4 months.[9] Only 3 of the 32 patients were alive longer than 1 year, and all of them were back on a BRAF or a MEK inhibitor. These preliminary data suggest that a BRAF inhibitor may not be the best initial therapy for some, if not most, patients with BRAF V600E mutations. A prospective trial is needed to study this question. A sequencing study is being planned by ECOG that has 2 arms: ipilimumab with crossover to vemurafenib at time of progression vs vemurafenib with crossover to ipilimumab at time of progression. The primary endpoint will be overall survival at 2 years. The study should tell us which is the best initial therapy for patients with BRAF mutant metastatic melanoma.

More Work to Be Done Medscape: Are there any potential downsides to combining immunotherapy and targeted therapy?

Dr Atkins: By combining immunotherapy and targeted therapy, the hope is to get the benefits of both worlds. But there are potential problems. Studies suggest that dacarbazine interferes with the immune effects of ipilimumab; however, preliminary data suggest that BRAF inhibitors might increase immune infiltration into tumors, converting the microenvironment from a noninflamed state to an inflamed state. Theoretically, this might mean that the combination of a BRAF inhibitor with immunotherapy might produce synergistic antitumor benefits. Medscape: What can you say to sum up where we are with melanoma immunotherapy in 2012? Dr Atkins: We have IL-2 and ipilimumab, and there are novel immunotherapies on the horizon, including the PD-1 antibody. We will need studies to refine optimal patient selection and identify the best combination treatments, including a BRAF inhibitor either alone or in combination with MEK inhibitors. The field has advanced, and in 2012 it is no longer futile to treat metastatic melanoma. There is a glimmer of hope on the horizon, but there is still a lot of work to be done.


“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


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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.