Abstract 5381: Activation and frequency of myeloid subsets in peripheral blood is associated with clinical outcome in prostate cancer patients treated with Prostate GVAX and anti-CTLA4

Abstract

Abstract Blockade of the CTLA-4 immune checkpoint can enhance anti-tumor responses and prolong survival, but it can also lead to the development of severe and potentially life-threatening immune-related adverse events (IRAE). To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity and can be used to recognize and select patients that will benefit from immune checkpoint blockade. We therefore performed extensive immune monitoring in a phase I/II dose escalation/expansion trial of combined Prostate GVAX (a GM-CSF-secreting allogeneic prostate cancer vaccine) and antiCTLA-4/ipilimumab immunotherapy in patients with Castration Resistant Prostate Cancer (CRPC). Here we report on the effects of the treatment on circulating myeloid cells and the identification of potential myeloid-related biomarkers. The GVAX/ipilimumab combination was clinically active with PSA declines of more than 50% in 5, and PSA stabilizations in 12 of 28 patients. Regressing bone and lymph node metastasis were observed in 2/5 PR patients. Flowcytometric monitoring of myeloid subsets in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed some striking differences between patients who benefited from therapy and patients who did not. Significant treatment-induced decreases of conventional and plasmacytoid Dendritic Cell subsets (cDC and pDC, respectively) were observed, which were paralleled by increased DC activation and recruitment to the vaccination sites. Treatment-induced activation of BDCA1/CD1c+ cDC and 6-sulfo LacNAc+ inflammatory DC was associated with significantly prolonged over-all survival (OS). In contrast, increased frequencies of CD11b+CD14−CD15+ granulocytic myeloid-derived suppressor cells (MDSC) and high pre-treatment levels of CD14+HLA-DRlo/− monocytic MDSC were associated with reduced OS. Together with similar analyses of T cell subsets, these studies have yielded an immune profile with predictive value for clinical outcome. The profile is characterized by pre- or on-treatment activation of immune effector subsets and low frequencies of regulatory/suppressive subsets. It may thus provide a potentially useful tool for patient selection and should be validated as such in other patient groups treated by antiCTLA-4 blockade. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5381. doi:1538-7445.AM2012-5381