CTL-associated antigen 4 (CTLA-4) blockade can induce tumor regression and improved survival in cancer patients. This treatment can enhance adaptive immune responses without an exogenous vaccine, but the immunologic biomarkers associated with improved clinical outcome in cancer patients are not fully established. A phase Ib trial in patients with metastatic, castration resistant prostate cancer (mCRPC) was performed combining ipilimumab with sargramostim (GM-CSF). In addition to evaluating ipilimumab dose, patients were followed clinically for response and overall survival, and for immunomodulation of circulating T cells. PSA declines of ≥ 50% and radiographic responses were observed at doses of ≥ 3 mg/kg/dose. Timing of clinical responses could be either immediate or delayed. Durable responses were also observed off treatment. A subset of patients experienced long-term survival with or without objective clinical responses. The relationship between T cell phenotype in peripheral blood and overall survival were examined retrospectively. We found that the treatment induced an increase in the levels of CD4+ effector T (Teff) cells, regulatory T (Treg) cells, PD-1+ CD4 Teff cells, and PD-1+ CD8 T cells. However, these increased levels were not associated with overall survival. Instead, low pre-treatment baseline levels of PD-1+ CD4 Teff cells were found to relate with longer overall survival. Furthermore, baseline levels of PD-1+ CD4 Teff cells from patients with shorter overall survival were higher than from cancer-free male controls. These results suggest that pre-existing expression of immunologic checkpoint marker, PD-1 on CD4 Teff cells may help to identify who may benefit from ipilimumab treatment.
- Received December 4, 2014.
- Revision received April 2, 2015.
- Accepted April 16, 2015.
- Copyright © 2015, American Association for Cancer Research.