T-cell checkpoint inhibitors have demonstrated dramatic clinical activity against multiple
cancer types, however little activity in patients with
prostate cancer. Conversely, an anti-
tumor vaccine was approved for the treatment of
prostate cancer, having demonstrated an improvement in overall survival, despite few objective disease responses. In murine studies, we found that PD-1 expression on CD8+ T cells increased following anti-
tumor vaccination, and that
PD-1/PD-L1 blockade at the time of immunization elicited greater anti-
tumor responses. Based on these data we initiated a pilot trial evaluating the immunological and clinical efficacy of
a DNA encoding
prostatic acid phosphatase (PAP) when delivered in combination with
pembrolizumab. 26 patients were treated for 12 weeks with
vaccine and received
pembrolizumab either during this time or during the subsequent 12 weeks. Adverse events included grade 2 and 3
fatigue,
diarrhea, thyroid dysfunction, and
hepatitis. Median time to radiographic progression was not different between study arms. 8/13 (62%) of patients treated concurrently, and 1/12 (8%, p=0.01) of patients treated sequentially, experienced PSA declines from baseline. Of these, two were over 50% and one was a complete PSA response. No confirmed CR or PR were observed, however 4/5 patients treated concurrently had measurable decreases in
tumor volume at 12 weeks. PSA declines were associated with the development of PAP-specific Th1-biased T cell immunity and CD8+ T cell infiltration in metastatic
tumor biopsy specimens. These data are the first report of a clinical trial demonstrating that the efficacy of an anti-
tumor vaccine can be augmented by concurrent PD-1 blockade.