Abstract B51: Circulating regulatory T-cell function and overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients treated with vaccine.

Abstract

Abstract Purpose: Targeted therapies using a receptor tyrosine kinase inhibitor Sunitinib has been reported to reduce levels of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs). MDSCs and Tregs can diminish active immunization against tumor-associated antigens in cancer patients. High levels of Tregs (CD4+CD25high FoxP3+CD127-) have been reported in peripheral blood mononuclear cells (PBMCs) of patients with several types of cancer. Treg numbers are not significantly increased in patients with prostate cancer (PCa) compared to healthy donors; However, Treg suppressive function is enhanced in PCa patients suggesting that Treg function may play an important role in immune modulation. We investigated the number and suppressive function Tregs in PBMCs from patients with mCRPC pre- and post-treatment with PSA-TRICOM vaccine in terms of baseline patient characteristics and overall survival (OS). Experimental Design: PSA-TRICOM is a poxviral-based vaccine that expresses 3 T-cell costimulatory molecules and prostate-specific antigen (PSA). Chemotherapy-naïve patients with mCRPC were treated monthly with PSA-TRICOM and 23 patients were evaluated for OS as well as frequency and suppressive function of Tregs on day 0 and after 3 monthly vaccines (around day 85). Treg function from PBMC was determined by the suppression of CD4+CD25- T-cell proliferation by Tregs. Results: OS for all 23 patients was 8.5 to 50.2 mos. By day 85 post vaccination, 14 of 23 patients (61%) showed decreases in Treg function. We found a significant correlation between OS and a decrease in the suppressive function of Tregs in PBMCs post-vaccination (Spearman's r = −0.454; P = 0.029). Of the 15 patients with an OS longer than the Halabi predicted survival (PS), 12 (80%) had decreased Treg function. Of 8 patients who had an OS less than the Halabi PS, 2 (25%) showed a decrease in Treg function by day 85. The Halabi nomogram is based on seven baseline disease characteristics: visceral disease, Gleason score, performance status, baseline PSA, LDH, alkaline phosphpatase, and hemoglobin. Patients with an OS greater than Halabi PS also had a significant increase in the effector:CTLA-4+ Treg ratio post-vaccination (P = 0.029 and P = 0.024, respectively). Conclusion: These data suggest a possible association between improved OS and a decrease in Treg function after treatment with PSA-TRICOM vaccine. Patients with an OS longer than Halabi PS appeared more likely to have decreased Treg function following vaccine. These results provide the rationale for the use of certain targeted therapies, such as Sunitinab, to facilitate the antitumor immunity in concert with prostate cancer vaccines such as PSA-TRICOM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B51.