It is theorized that if antigen presentation could be improved, the immunostimulatory effects of CTLA-4 blockade could be augmented with improvements in clinical response. To that end, UCSF conducted a phase I clinical trial of ipilimumab in combination with GM-CSF, a cytokine that has been demonstrated to enhance the functional activities of effector cells, including dendritic cells (DC), neutrophils, and monocytes, in chemotherapy-naïve men with CRPC (Protocol 6032).32 Exposure to GM-CSF increases class II MHC expression on dendritic cells and is thought to lead to increased antigen presentation to T cells, stimulating T cell responses, although this mechanism has not been confirmed. We have extensively studied the effects of treatment demonstrating a dose-response relationship in the activation of CD4 and CD8 T cells. Moreover, the expansion of activated (CD25+CD69+) CD4 and CD8 T cells seen with this GM-CSF/ipilimumab combination trial was higher than that seen with GM-CSF or ipilimumab monotherapy seen in our other trials in prostate cancer patients.