Vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) augments tumor immunity in murine models through improved tumor antigen presentation by mature CD11b+ dendritic cells and macrophages. CD4+ and CD8+ T cells, CD1d-restricted invariant NKT cells, and antibodies mediate protective immunity. We have performed several Phase I clinical trials of this immunization strategy, using adenoviral mediated gene transfer to engineer autologous tumor cells to secrete human GM-CSF, in patients with advanced melanoma, non-small lung carcinoma, ovarian carcinoma, and myeloid leukemia. These investigations have demon strated that vaccination increases tumor immunity in the majority of subjects, as distant metastases become densely infiltrated with T and B cells that accomplish extensive tumor necrosis. Antibody based-expression cloning technologies have revealed a large number of novel targets of these vaccine-induced responses, with evidence of a coordinated antigen-specific cellular and humoral reaction. Despite improved immunity, however, the majority of vaccinated patients eventually succumb to progressive disease. While the evolution of antigen-loss variants presents one obstacle to durable tumor control, negative immune regulation constitutes an additional major challenge. In preliminary clinical studies, the administration of a fully human monoclonal antibody that blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) to previously vaccinated patients evokes additional tumor destruction with lymphocyte and granulocyte infiltrates and the disruption of the tumor vasculature. CTLA-4 blockade may also breach tolerance to normal tissues, as indicated by the development of autoimmunity. A key issue of ongoing investigation is to determine whether tumor destruction and serious autoimmunity can be dissociated. Studies of patients responding to CTLA-4 blockade have begun to clarify the ways in which protective immunity can be safely induced and, in so doing, immunosuppressive mechanisms reversed.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]