Abstract 2849: Pharmacodynamic biomarkers of anti-PD-L1 activity in pre-clinical mouse tumor models.

Abstract

Abstract Programmed cell death 1 ligand 1 (PD-L1, CD274, B7-H1) is an immune checkpoint molecule expressed in various tissues, including multiple peripheral blood mononuclear cells and placenta. PD-L1 binds its receptor PD-1 on activated T cells to negatively regulate their function in both physiological and pathological conditions. PD-L1 also binds B7.1 (CD80), further down modulating immune responses. Importantly, numerous cancers resist T-cell mediated cytotoxic activity by over-expressing PD-L1. The goal of this study was to identify pharmacodynamic biomarkers of response to agents blocking PD-L1/PD-1 pathway in pre-clinical models. CT-26 and MC-38 murine mouse tumor models were selected for this analysis, based on their PD-L1 expression and in-vivo sensitivity to anti-PD-L1 treatment. Tumors have been collected at various time points following treatment with an antibody blocking PD-L1 binding to PD-1 and B7.1. Subsequently, FACS, IHC, qPCR and a multiplex qPCR-based expression assay measuring a panel of ∼90 immune-related biomarkers have been used to evaluate changes in major immune cell subtypes and their activation status. We show that the intra-tumoral immune environment undergoes a time-sensitive dynamic modulation in response to PD-L1 pathway blockade, including an early and potent Th1 driven CTL response, as measured by relevant markers. Additionally, our findings show that targeting PD-L1 in pre-clinical tumor models can reinvigorate the host immune responses against the tumor and lead to T-cell mediated tumor killing. Our data also support identification of potential pharmacodynamic biomarkers that can be used to monitor activity of agents targeting the PD-L1 pathway in the clinic. Citation Format: Marigold Boe, Mahrukh Huseni, Brittany Jiang, Hartmut Koeppen, Heather Maecker, Bryan Irving, Priti Hegde, Marcin Kowanetz. Pharmacodynamic biomarkers of anti-PD-L1 activity in pre-clinical mouse tumor models. [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 2849. doi:10.1158/1538-7445.AM2013-2849