CTLA-4 blockade-based immunotherapy for prostate cancer

Abstract : CTLA-4 is an inhibitory molecule on T cells that induces T cell downregulation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth and survival factor for dendritic cells. The safety of combining GM-CSF with CTLA-4blockade in prostate cancer patients is being investigated in an ongoing phase I trial. Methods: Sequential cohorts of 3-6 patients receive GM-CSF 250mug/m2/d subcutaneously on days 1-14 of a 28-day cycle withescalating doses of anti-CTLA antibody on day 1 of each cycle x 4. Patients are monitored for clinical autoimmunity with T celiphenotyping performed. Results: Twenty patients have been treated to date. Dose-limiting toxicity (DLT) was not observed in the initial CTLA-4 antibody doselevel. Two DLTs consisting of a vertebrobasilar TIA possibly related to therapy and a generalized rash requiring steroids wereobserved in the second and third dose levels respectively resulting in expansion of each to 6 patients. No laboratory evidence ofautoimmunity has been observed in any patient. Expansion of monocytes 1 dendritic cells and upregulation of PBMC activation markershave been seen consistent with known GM-CSF effect. A dose response relationship has been seen between anti-CTLA-4 dose andactivation of both 004+ and 008+ T cells in the blood. These effects were increased compared to effects seen with anti-CTLA4treatment alone on a separate trial. T cell interferon-gamma production and lytic activity were also enhanced in circulating antigen-specific CD8+ T cells after this combination immunotherapy. Conclusions: CTLA-4 blockade and GM-CSF has demonstrated preliminary safety in advanced prostate cancer. Accrual andimmunologic analyses are ongoing. A phase II trial is being planned of this combination in vaccination-failure prostate cancer patients.