F. Stephen Hodi, Jr., MD
Director, Center for Immuno-Oncology
Professor of Medicine, Harvard Medical School
Center for Immuno-Oncology
Office phone: 617-632-5055
Website: Patient Gateway
Preferred contact method: office phone
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Gene therapy for cancer, Melanoma, Tumor immunology
Area of ResearchCombination Immunotherapies for Cancer
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
Dr. Hodi is the Director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber/Brigham and Women's Cancer Center and Professor of Medicine at Harvard Medical School. He received his MD degree from Cornell University Medical College in 1992. Dr. Hodi competed his postdoctoral training in Internal Medicine at the Hospital of the University of Pennsylvania, and Medical Oncology training at Dana-Farber cancer Institute where he joined the faculty in 1995. His research focuses on gene therapy, the development of immune therapies, and first into human studies for malignant melanoma. Dr. Hodi is a member of the National Comprehensive Cancer Network, the American Society of Clinical Oncology, the Eastern Cooperative Oncology Group Melanoma Committee, the International Society for the Biological Therapy of cancer, and a founding member of the Society for Melanoma Research.
- Mentoring Clinical Scientist Development Award, 1998
ResearchCombination 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.