Abstract 498: A combination trial of vaccine plus ipilimumab in patients with metastatic castration-resistant prostate cancer: immune correlates.
Authors: Jochems Caroline , Tucker Jo A. , Madan Ravi A. , Dahut William L. , Gulley James L. , Schlom Jeffrey , Tsang Kwong-Yok 
Published: August 2014

Purpose: We recently published (Lancet Oncol. 2012;13(5):501-8) the clinical results of a trial combining ipilimumab (CTLA-4 blockade) with PSA-TRICOM, a viral vector vaccine containing transgenes for prostate-specific antigen (PSA) and three costimulatory molecules, in patients with metastatic castration-resistant prostate cancer. Thirty patients were treated with an escalating dose of ipilimumab, and fixed dose of vaccine. Of the 24 chemotherapy-naïve patients, 58% had a PSA decline from baseline. Combination therapy did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Here, we evaluated the correlations of 30 immune cell subsets and clinical outcome in an effort to identify relevant biomarkers for immune monitoring of patients in clinical immunotherapy trials.

Experimental Design: PBMCs were collected before therapy and at 70 days post initiation of therapy, and phenotyped by flow cytometry for T cells, regulatory T cells (Treg), natural killer (NK) cells and myeloid derived suppressor cells (MDSC). Inducible TH17 cells and intracellular IFNγ were evaluated after stimulation. Correlations of overall survival (OS) and immune cell subsets prior to treatment and 70 days post initiation of therapy, as well as OS and the change in a given immune cell subset were performed.

Results: There were significant correlations with OS before therapy; Fewer monocytic MDSC correlated with longer survival (R= -0.72). There was a negative correlation with CD8+ central memory cells (CD8cm) (R= -0.64), and a positive correlation with the more activated PD1+ CD8cm subset (R= 0.67).

At 70 days post initiation of therapy, high CD4cm (R= 0.54) and low CTLA-4+ Tregs (R= -0.53) correlated with longer survival.

For correlations of OS and the change in a given immune cell subset, we found significant correlations for increased activated immature NK cells (R= 0.94) and decreased immature NK cells (R= -0.82). Additionally, a larger decrease in immunosuppressive cells such as CTLA-4+ Tregs and non-lineage MDSC after treatment correlated with increased OS (R= -0.37 and -0.83, respectively).

Conclusions: The most striking result was the negative correlation at baseline of OS with the level of monocytic MDSC. Moreover, a decrease after therapy in the levels of CTLA-4+ Tregs and non-lineage MDSC correlated with increased OS. These results will be further evaluated in larger immunotherapy trials.

Citation Format: Caroline Jochems, Jo A. Tucker, Ravi A. Madan, William L. Dahut, James L. Gulley, Jeffrey Schlom, Kwong-Yok Tsang. A combination trial of vaccine plus ipilimumab in patients with metastatic castration-resistant prostate cancer: immune correlates. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 498. doi:10.1158/1538-7445.AM2013-498