Immunotherapy advances in targeting melanoma

Vienna, Austria - As the use of antibody-based immunotherapy has advanced the treatment of lymphoma, breast cancer and colon cancer, Soldano Ferrone, M.D. of Roswell Park Cancer Institute, Buffalo, N.Y., is optimizing an immunotherapy approach to the treatment of melanoma based on the induction of antibodies which recognize a membrane-bound antigen expressed on melanoma cells.

"We believe that application of antibodies that recognize antigens expressed on melanoma cells are a viable approach because it is not affected by the limitations of strategies that rely on the utilization of T cells as effector cells. With that in mind, several years ago we developed a strategy, which would elicit antibodies in patients with melanoma. These antibodies recognize a proteoglycan antigen, named the high molecular weight-melanoma associated antigen (HMW-MAA), which is expressed on melanoma cells. In a phase 1 clinical trial, we found an association between development of HMW-MAA-specific antibodies and survival prolongation."

The high expression of this proteoglycan on melanoma cells in a high percentage of melanoma lesions and its restricted distribution in normal cells makes it an attractive target.

"We have data that demonstrates that HMW-MAA-specific antibodies can suppress the growth of human melanoma cells transplanted in immunodeficient mice," Dr. Ferrone tells Dermatology Times. "We also know that the antibodies are not very effective in mediating lysis of melanoma cells through immunological mechanisms. Therefore we believe that the HMW-MAA-specific antibodies elicited in patients with melanoma have an impact on the biology of melanoma cells by inhibiting the function of the target antigen. This antigen plays a role in the interactions of melanoma cells with the extracellular matrix and in the migration of melanoma cells. Therefore binding of antibodies to HMW-MAA is likely to have a detrimental effect on the tumor, since it inhibits the ability of malignant cells to interact with the extracellular matrix and to migrate. As a result, there is a reduction in the volume of the tumor and in the ability of melanoma cells to metastasize."

Beneficial effect The apparent beneficial effect of HMW-MAA-specific antibodies on the clinical course of the disease in patients with melanoma has stimulated interest in the development of strategies to optimize the immunogenicity of vaccines to elicit HMW-MAA-specific antibodies.

"We are working on improving our ability to elicit high affinity, high titer antibodies to the HMW-MAA in patients with melanoma with the expectation that this will improve their ability to control melanoma tumor growth," Dr. Ferrone says. "In order to do this, we are taking advantage of crystallographic studies, which have provided information about the structure of the vaccine that we are utilizing. Using this structural information, we want to modify the vaccine in a rational way so that it, hopefully, becomes more immunogenic."

Future research "This is a very good example of how, by applying basic research to a clinical problem, a clinical investigator can come up with a strategy which may have an impact on the clinical management of melanoma," Dr. Ferrone explains. "It is also important to recognize that when monoclonal antibodies were first developed there was a lot of enthusiasm in applying them for the treatment of melanoma. This was followed by skepticism because of the disappointing results obtained in several clinical trials. However, now that we better understand that the activity of the antibodies is not only limited to immunological mechanisms but may also involve non-immunological mechanisms, we can apply basic research to come up with therapeutic strategies."

Dr. Ferrone and his colleagues are currently in the process of doing further studies involving these immuno-therapeutic approaches. Once they have obtained data in experimental animal model systems, they will be able to apply the information obtained to implement a clinical trial.