Abstract 5025: Dissecting the dynamics of anti-PD1 immunotherapy in preclinical tumor models

Abstract

Abstract MK-3475 is an antagonistic humanized IgG4 anti-PD1 antibody currently in late stage clinical development for the treatment of cancer. MK-3475 exerts its anti-tumor effect through blocking the interaction of the immune inhibitory molecule PD-1 with its ligands. MK-3475 does not bind to mouse PD-1. Therefore, we generated a surrogate antibody, mDX400 for use in preclinical rodent models. In multiple syngeneic tumor models, treatment with mDX400 murinized anti-mouse antibody results in complete and durable tumor regression. We have used mDX400 as a mouse equivalent of MK-3475 to aid in our understanding of the cellular and molecular dynamics of anti-PD1 immunotherapy. In the current study, we examined peripheral and intratumoral lymphoid compartments pre- and post-mDX400 treatment. The data indicated that: 1. Anti-tumor efficacy was primarily driven by the level of PD-1 receptor blockade in tumor, but not blood. 2. An altered molecular signature, including significant upregulation of genes involved in monocyte, B- and T-cell activation and differentiation, was observed post-treatment in the tumors, but not peripheral blood or draining lymph nodes, of responding animals. 3. Tumor-specific immune memory was evident, as assessed by ultrahigh-throughput DNA sequencing of TCR CDR3 region, following successful treatment with mDX400. These data provide insights into the molecular dynamics following anti-PD1 immunotherapy and will guide hypothesis generation for biomarkers to inform our clinical strategy. In addition, the cellular and molecular pathways that predominate in preclinical tumor models insensitive to anti-PD1 immunotherapy are being evaluated. These types of studies may inform us on potential therapies that can be combined with MK-3475 to expand the therapeutic benefit of this biologic. Citation Format: Venkataraman Sriram, Michael E. Bigler, Holly Cherwinski, Erin Murphy, Terrill K. McClanahan, Joseph H. Phillips. Dissecting the dynamics of anti-PD1 immunotherapy in preclinical tumor models. [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 5025. doi:10.1158/1538-7445.AM2014-5025