Abstract 5012: A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: Immune correlates
Authors: Coyne Geraldine O'Sullivan , Jochems Caroline , Heery Christopher , Singh Harpreet , Surolia Ira , Riley Robin , Madan Ravi , Dahut William , Steinberg Seth , Gulley James , Schlom Jeffrey 
Published: May 2015

Abstract
Background: We present updated survival and immune cell data analysis following our published results of a Phase I clinical trial combining ipilimumab with PSA-TRICOM vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC). Ipilimumab is an antagonistic monoclonal antibody binding cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and CD80 on antigen-presenting cells. We assessed the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. We also evaluated 36 immune cell subsets pre- and post-therapy. Methods: We previously carried out a phase 1 dose-escalation trial, and subsequent expansion phase, assessing safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-TRICOM vaccine. Thirty patients were treated with escalating ipilimumab and a fixed dose of vaccine. Patients with mCRPC received 2×108 plaque-forming units of recombinant vaccinia PSA-TRICOM subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×109 plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Primary goal was to assess the safety of the combination. For analysis of immune data, peripheral blood mononuclear cells were collected before therapy, at 13 days and at 70 days post initiation of therapy, and phenotyped by flow cytometry for subsets of T cells, regulatory T cells, natural killer cells and myeloid derived suppressor cells. Associations between overall survival (OS) and immune cell subsets prior to treatment, and changes in a given immune cell subset 70 days post initiation of therapy were evaluated. This study was registered: ClinicalTrials.gov, NCT00113984. Results: As previously reported, of 24 chemotherapy-naïve patients, 58% had a PSA decline, of which six were ≥ 50%. Combination therapy didn't exacerbate immune-related adverse events associated with ipilimumab. Median OS was 2.63 years (1.77-3.45). There were trends towards associations for longer OS and certain immune cell subsets before immunotherapy: lower PD-1+Tim-3NEGCD4em (P = 0.005, adjusted P = 0.010), higher PD-1NEGTim-3+CD8 (P = 0.002, adjusted P = 0.004), and a higher number of CTLA-4NEG Tregs (P = 0.005, adjusted P = 0.010). We also found an increase in Tim-3+ natural killer cells post- vs. pre-vaccination associated with longer OS (P = 0.0074, adjusted P = 0.015). Conclusions: Given there are no clinical discriminators of outcome until OS data is available, a potential prognostic marker set that can be assessed soon after treatment initiation would be beneficial. These results should be considered as hypothesis generating, and further evaluated in larger trials.
Citation Format: Geraldine O'Sullivan Coyne, Caroline Jochems, Christopher Heery, Harpreet Singh, Ira Surolia, Robin Riley, Ravi Madan, William Dahut, Seth Steinberg, James Gulley, Jeffrey Schlom. A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: Immune correlates. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5012. doi:10.1158/1538-7445.AM2014-5012