Innovations in treating melanoma

April 1, 2007

Future interventions that target multiple inhibitory pathways will be the ones most likely to succeed.

Washington - "Melanoma is not a magical cancer," says Marie-France Demierre, M.D., speaking at the 65th Annual Meet-ing of the American Academy of Dermatology, here.

Host immune defenses can influence the course of melanoma, both regionally and systemically.

"In rare instances that may take form in spontaneous remission, but more commonly it plays out through partial regression or slower progression of disease."

Tumor recognition, neutralization

The immune system can recognize and neutralize tumor cells.

Key to that process is effective presentation and recognition of antigen to the T cell. New findings over the past five years have highlighted the importance of HLA types to both the response to tumors and the response to a vaccine to stimulate immune recognition of that tumor.

As a result of this work, scientists now know that a vaccine "may not work in 60 percent of the patients because they do not have the HLA-2 that allows you to present the antigen."

Dr. Demierre tells Dermatology Times that early cancer vaccine trials did not take HLA into account; they did not stratify patients by HLA type.

Thus, "We cannot say much about the negative results of those early trials."

It may well be that the vaccine was effective in a subset of patients with the appropriate HLA to adequately express that antigen.

Old and new approaches

She says the Allovectin-7 vaccine (Vical) builds upon the fact that HLA B7 is lost in melanoma.

The vaccine plasmid enters the antigen-presenting cell, presents what is missing, and stimulates immune recognition so that the cancerous cells are destroyed. The vaccine is in phase 3 clinical trials.

The irony is that the "gold standard" of modern medical research, the randomized controlled trial, may not be applicable to the emerging field of medicine that is personalized to the genetic traits of the individual patient.

Dr. Demierre believes that the key to future therapy will be to better characterize both the patient and the disease to select the most appropriate intervention. And often, that intervention may be an immunomodulating strategy based upon an autologous source of material that is manipulated ex vivo and returned to the patient to assist the host defense.

Cytotoxic T-cell lymphocyte antigen 4 (CTLA4) is a signaling molecule that "calms down the immune function" of CD8 cells.

Tumor cells produce CTLA4 as one of the mechanisms to avoid destruction by the immune system. Underexpression of the molecule results in autoimmune disease and also correlates with tumor regression.

Dr. Demierre says, "We are starting to realize that maybe what may be keeping some of our melanoma patients going is their autoimmune disease."

Based in part upon this insight, a monoclonal antibody has been created that neutralizes CTLA4. In preclinical studies, it resulted in tumor cells being recognized and lysed by the immune system. Dr. Demierre explains one challenge with this approach in vivo will be to find the right balance so that melanoma is recognized, without triggering a severe autoimmune response.

Head it off at the pass

Chemoprevention is another broad strategy being developed to reverse or suppress melanoma in its early stages before it becomes visible, and to forestall recurrence.

Dr. Demierre sees the approach as a complement to prevention strategies. The RAS signaling pathway promotes proliferation and is activated in about a third of melanomas. It is a target for intervention.

She says, "In advanced patients, B-RAF and C-RAF inhibitors, in combination with chemotherapy, have been shown to promote apoptosis."

Dr. Demierre says, "It is possible that an early melanoma lesion may be caused by the dysfunction of a single pathway, but I think that more advanced disease is probably the result of multiple pathways" gone awry.

That has led her to posit that future interventions that target multiple inhibitory pathways will be the ones most likely to succeed.

She concludes, "I'm excited about vaccines and chemoprevention, since there is an opportunity for dermatologists to take an active role in the management of their melanoma patients, as opposed to taking a secondary role to oncologists."