My laboratory studies the molecular and cellular mechanisms underlying the generation of anti-tumor immunity. We have demonstrated that vaccination with irradiated tumor cells engineered to secrete GM-CSF stimulates potent, specific, and long-lasting anti-tumor immunity in murine models and patients with diverse hematologic and solid malignancies. CTLA-4 antibody blockade further increases anti-tumor memory responses. To identify the target antigens underlying tumor destruction, we used sera and T cells from vaccinated patients to screen tumor cell-derived cDNA expression libraries. Several rejection antigens with critical roles in transformation have been characterized thus far, including a novel inhibitor of apoptosis protein, angiogenic cytokines, and components of the NKG2D pathway. Efforts to characterize the therapy-induced antibodies with functional activity are underway. We are also developing new cancer vaccine platforms using engineered material scaffolds and small molecule inhibitors of the IAP family.
We have also generated mice lacking GM-CSF, interleukin-3, and interferon-gamma through gene targeting techniques. These animals spontaneously develop at high frequency hematologic and solid neoplasms within a background of persistent infection and inflammation. Mechanistic studies have revealed dual roles for immunity in tumor promotion and protection in this system.