Treating colon cancer with a melanoma vaccine? Preposterous?

Dr. Donald Morton and his group have never been afraid to think outside the box. While the rest of us were debating whether to do elective node dissections for melanoma, he developed a technique to identify nodal micrometastases in the “sentinel” node, revolutionizing the management of stage I and II melanoma in the process. But has he gone too far this time? After all, giving patients with colon cancer a melanoma vaccine! 1 That’s crazy—isn’t it? Maybe not. It certainly bucks the current trend toward ever more precisely defined single antigen vaccines, such as the rash of designer peptides that are not merely disease-specific but actually restricted to use in specific subsets of patients based on HLA expression. So giving patients a “gamish” of melanoma cells in hope of engendering an immune response to colon cancer antigens would seem to be proceeding in the opposite direction: firing blindly at the immune system and hoping a ‘golden bullet’ magically hits the target. Nonetheless, the limitations of defined-antigen vaccine strategies are becoming apparent, 2,3 and evidence that polyvalent, autologous, and allogeneic tumor vaccines can mediate an effective antitumor immune response is growing. 4,5 The question is no longer “If?” but “How?” Limitations of Defined Antigen Vaccines Human tumors develop in a series of evolutionary steps, during which time they evade the immune system’s surveillance mechanisms. Thus, every clinically detectable tumor is already adept to some degree at disguising itself from the immune system. Antigenic heterogeneity is the rule in tumors: even within strongly antigen-rich tumors there are at least some cells that do not express the target antigen. Moreover, most tumors are eventually capable of down-modulating antigen expression in the face of sustained immune attack. Although it is clear that on occasion immunization with a single, defined antigen can result in regression of even extensive tumor, this is the exception and not the rule. So far, successes of immunotherapy with single antigen vaccinations have been virtually entirely restricted to malignant melanoma patients. The possibility exists that melanoma is a unique tumor arising in a regionally immunocompromised setting (ultraviolet radiation-exposed skin), not readily generalizable to other solid tumors. Even if a tumor lacks antigen expression on a subset of its cells, a defined antigen vaccine can still induce regression of advanced disease by killing the majority population of antigen-expressors. Ultimately, unless a more generalized immune reaction occurs (“epitope spreading”), the antigen-negative population will grow out and cause clinical relapse. This limitation is particularly glaring in the adjuvant therapy setting, where cure and not transient reduction of tumor burden is the goal. It may be that this phenomenon explains the results of a recent phase III clinical trial in which a defined antigen vaccine (purified GM2 ganglioside conjugated to keyhole limpet hemocyanin) that achieved high levels of IgG and IgM antibody induction failed to match standard therapy with high-dose interferon-alfa 2b in high-risk melanoma patients. 2