Friday, May 29, 2009

Despite Past Disappointments the Future of Melanoma Therapy Appears Bright Melanoma..Jim Breitfeller

Ahmad Tarhini, MD, MSc
Assistant Professor of Medicine
Department of Medicine
Division of Hematology/Oncology
University of Pittsburgh School of Medicine

Annually, about 8,000 patients are found to have metastatic melanoma presenting as recurrence of an earlier primary melanoma, and this number closely approximates the annual number of deaths from the disease. This statistic illustrates the lack of progress that has been made in the treatment of stage IV melanoma over the past several decades. As very nicely reviewed in this issue of ONCOLOGY by Bhatia et al, no therapeutic agent has been shown in randomized clinical trials to prolong survival in patients with metastatic melanoma. Chemotherapy with single-agent dacarbazine is the only US Food and Drug Administration (FDA)-approved chemotherapy agent for metastatic melanoma.

Role of Immunity
Immunity to melanoma appears to be important for disease control in the adjuvant and advanced-disease settings. Spontaneous regression has been reported in melanoma, suggesting a role for host immunity. This possibility is indirectly supported by the regular presence of lymphoid infiltrates at the site of primary melanoma, a phenomenon that is frequently associated with histopathologic evidence of tumor regression.

Host cellular immune response within melanoma has potential prognostic and predictive significance. T-cell infiltrates in primary melanoma are prognostic of disease outcome,[1] and T-cell infiltrates within regional nodal metastasis predict benefit from interferon alfa-2b (IFNα2b, Intron A) therapy.[2-4] Immunologic approaches have yielded the only newly FDA-approved agent for metastatic disease in 30 years—high-dose bolus interleukin-2 (IL-2, Proleukin). This therapy is based on durable responses seen in some patients with metastatic melanoma, but with an associated high toxicity rate and cost.

Novel Agents
Currently the optimal approach to the management of patients with metastatic melanoma is treatment on clinical trials in an effort to maximize treatment options and provide access to promising therapeutic approaches for this disease. The future of melanoma therapy appears promising, with many novel experimental agents being tested in clinic, building upon the continuously deepening knowledge of host immunity and molecular circuitry of the tumor. Cancer vaccines continue to be actively tested in melanoma (peptide vaccines, genetic heat shock proteins, and dendritic cell–based vaccines). Molecular approaches to deranged signaling pathways and proapoptotic strategies are also being widely investigated. A phase III intergroup trial coordinated by the Eastern Cooperative Oncology Group (E2603) was recently completed, in which 800 patients with chemotherapy-naive metastatic melanoma were randomized to carboplatin and paclitaxel with either sorafenib (Nexavar) or placebo. The results of this trial are awaited. The roles of several critical regulatory elements of the immune system have recently been elucidated, providing insight into the disease process and new targets for overcoming tolerance. Enhanced expression of costimulatory molecules on the surface of dendritic cells is one approach to enhancing the presentation of tumor-associated antigens. This can be achieved through stimulation of dendritic cell receptors such as CD40 and Toll-like receptor 9 (TLR9).[57] Another approach is to enhance or prolong T-cell activation by blocking negative-signaling receptors such as CTLA4.[8] New strategies, such as the administration of oligodeoxynucleotides that activate TLR9, monoclonal antibodies (mAbs) that activate CD40 or block CTLA4, and costimulatory antibodies to CD137, or targeting regulators of apoptosis such as PD1 (programmed death-1)[9] may provide more effective immunotherapies that might overcome tumor-induced tolerance.

The closure of the tremelimumab phase III melanoma study for “futility” came as a surprise to many investigators, given clinical observations of durable benefits in some patients. The 1-year survival rate of > 50% for tremelimumab and the median survival of 11.7 months (compared with 10.7 months for chemotherapy) were also surprising, although this may have been the result of the selection criteria for this study. The exclusion of patients with 2× upper limit of normal lactate dehydrogenase (LDH) blood values and crossover of patients in the control arm to another anti-CTLA4 mAb may also have played a role in the results, but this remains to be clarified, and more mature survival and response data are anticipated. Results of the phase III studies testing CTLA4 blockade with ipilimumab (as a single agent or in combination with dacarbazine in one study, and administered in conjunction with the gp100 peptide vaccine in another study) are eagerly anticipated.

The further development of novel agents in melanoma will likely include combinations based on strategies for overcoming tumor-induced immune suppression. Preliminary data from combination biotherapy involving CTLA4-blockade with high-dose IFN-α2b[10] and dendritic cell–based vaccination are promising in melanoma.[9,11,12]

Future research should incorporate the study of biomarkers to predict therapeutic benefit into randomized trials. This may lead to the identification of biomarkers enabling personalized therapy, which has become a Holy Grail of sorts, particularly in melanoma, for which standard options are so limited. Although subsets of melanoma patients clearly benefit from different approaches, these positive results have not been reproduced in classic randomized trials. Some clues could be found in the now repeatedly reported association between the induction of autoimmunity and therapeutic benefit with IFN-α2b, IL-2, and CTLA4-blocking mAbs.[13] Revealing investigations might involve the induction of autoimmunity to a broad array of endocrine and tumor markers as biomarkers of therapeutic benefit.

In addition, researchers may identify immunogenetic factors that predispose patients to induction of autoimmunity by these agents (eg, human leukocyte antigen genotype, polymorphisms of the CTLA4 gene and the FOXP3 transcription factor loci, as well as other immunogenetic markers). Multiplex analysis—encompassing cytokines, chemokines, angiogenic and growth factors, soluble receptors, signal transduction molecules, and other immune and endocrine markers—in relation to patient outcome could also be studied, building upon promising early results.[13,14] Important data along these lines could be provided from melanoma patients treated with adjuvant high-dose IFN-α2b (E1697), and planned adjuvant trials with CTLA4 blockade (ipilimumab, E1609).


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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.