Combination Immunotherapies for Cancer
The ability to manipulate genes that encode potential immunomodulators, such as cytokines and tumor antigens, has opened a new era of research. Poorly immunogenic murine tumor systems demonstrate that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) generates potent, specific, and long-lasting immunity.
To test this strategy in patients with advanced melanoma, our laboratory performed a clinical trial of vaccination with lethally irradiated, autologous melanoma cells expressing human GM-CSF. Vaccination elicited a striking infiltrate of large numbers of lymphocytes, plasma cells, macrophages, and eosinophils, resulting in tumor destruction, fibrosis, and edema. These results provide a solid foundation for undertaking a molecular analysis of the melanoma antigens stimulating specific T and B cell responses in vaccinated patients. Candidate antigens are identified from screening with autologous sera of a complementary DNA expression library constructed from vaccinated patients' tumor cell lines. For a number of antigens evaluated, potent humoral immune responses are associated with immune-mediated destruction of diverse tumors - offering the promise of future antigen-directed therapies.
One mechanism that may limit the therapeutic potency of cancer vaccines is the attenuation of T cell function by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Striking therapeutic synergies have been observed between CTLA-4 blockade and GM-CSF-secreting tumor cell vaccines in murine models of melanoma, breast cancer, and prostate cancer. Based on these preclinical data, we initiated a phase I clinical trial of single administration of anti-CTLA-4 antibody (MDX-CTLA-4) in previously vaccinated patients with metastatic melanoma or ovarian cancer. Of the nine subjects treated, three had received irradiated, autologous GM-CSF-secreting melanoma cells; four patients with metastatic melanoma had received vaccinations against melanosomal antigens; and two patients with ovarian cancer had received autologous GM-CSF-secreting cells.
The three patients who received autologous GM-CSF-secreting melanoma cell vaccines demonstrated extensive tumor necrosis associated with hemorrhage and immune infiltrates in response to MDX-CTLA-4. In contrast, four of four patients who received vaccinations for melanosomal antigens failed to develop an immune infiltrate or tumor necrosis in response to MDX-CTLA4. The two patients with ovarian cancer had either a decrease or plateau to their CA-125 tumor marker levels following treatment with MDX-CTLA-4.
The immune infiltrates and massive tumor destruction witnessed in patients who had received MDX-CTLA-4 and GM-CSF-secreting cell vaccines suggest synergistic antitumor effects. This work provides the basis for additional studies to verify these observations in additional tumor types and to test combination immunotherapy modalities.