Management of Metastatic Cutaneous Melanoma

Although chemotherapy regimens can produce objective responses in patients with metastatic melanoma, curative responses are extremely rare. It is therefore of significant interest that the majority of complete responses to immunotherapy with high-dose interleukin (IL)-2 (Proleukin) alone are durable and probably curative.[1] In our own series of 182 patients with metastatic melanoma, 12 (7%) experienced a complete response and only 2 have had a disease recurrence with a median follow-up of 11.9 years. The remaining 10 patients remain in complete response at 133 to 211 months, and no patient with a complete response has recurred beyond 12 months. Responses have occurred at all parenchymal organ sites, and there is little relationship between the bulk of disease and the likelihood of achieving a complete response. Treatment- related side effects can be readily managed, and treatment-related mortality in our series of patients with metastatic cancer is less than 1%.[2] Immunotherapy Research
IL-2 has no direct effect on cancer cells, and thus, all of its anticancer activity is dependent on the ability of IL-2 to modulate host immune reactions against the growing cancer. The most important principle of cancer therapy that emerged from these clinical studies was the demonstration that immune manipulations can cause the regression of established, invasive, bulky cancers in humans and that this therapy can eliminate the last cancer cell. These findings have stimulated considerable efforts to understand the immunologic principles underlying these responses, with the hope of gaining insights that could lead to improved response rates and enable the successful application of immunotherapy to the treatment of other cancer types. The identification of T lymphocytes that could recognize melanoma cells led to the identification and characterization of dozens of melanoma antigens as well as antigens expressed on a wide variety of common epithelial cancers.[ 3] Multiple clinical trials have attempted to immunize cancer patients with these antigens using either peptides, proteins, or plasmids or recombinant viruses encoding them. Although active immunization (cancer vaccines) can generate endogenous T cells that recognize cancer antigens, thus far these efforts have been unsuccessful in reproducibly mediating tumor regression. Only rare and sporadic responses have been seen, and the factors enabling the tumor to escape from these immune reactions represents an active area of investigation. Possible mechanisms include the presence of an insufficient number of antitumor cells, weak avidity of tumor recognition, the inability of the tumor to activate the T cells, and the presence of regulatory lymphocytes that suppress the ability of the lymphocytes to function. Cell Transfer Therapy
An alternative approach to immunotherapy that can overcome many of these obstacles is cell transfer therapy. With this approach, large numbers of highly avid, already activated, in vitro-generated T cells with antitumor activity are transferred to the cancer-bearing patient. An element essential to the success of this approach is the depletion of host endogenous lymphocytes using a nonmyeloablative chemotherapy prior to cell trans- fer that can eliminate host regulatory cells and make "space" for the transferred cells. Using this approach, approximately 50% of patients with metastatic melanoma experience an objective cancer regression.[4] For the first time, substantial persistence of the transferred cells has been demonstrated, and in some patients, up to 80% of all circulating CD8 lymphocytes have antitumor activity derived from the infused cells. Cancer regression is highly correlated with persistence of the transferred cells. These experimental approaches are under active development in the Surgery Branch of the National Cancer Institute. The genes encoding T cell receptors from lymphocytes that mediate tumor regression have been cloned, and transduction of these genes into the peripheral lymphocytes of patients can invest these cells with potent antitumor activity.[5] Cell transfer protocols using these transduced cells have begun, as are studies to extend this approach to the treatment of additional tumor types.