Evaluation Of The Antitumor Activity Of Anti-Pd-1 Immunotherapy As A Single Agent And In Combination With Approved Agents In Preclinical Tumor Models

Pembrolizumab (MK-3475), a humanized monoclonal IgG4 antibody against programmed death receptor 1 (PD-1), is currently being studied in clinical trials across more than 30 types of cancers. To further support the clinical development of pembrolizumab and to aid the mechanistic understanding of anti-PD-1 immunotherapy, we generated a surrogate PD-1-blocking antibody (muDX400). We have used muDX400 to determine the antitumor activity, pharmacokinetics, and pharmacodynamics of PD-1 inhibition in multiple preclinical syngeneic tumor model systems. Response to muDX400 treatment in several syngeneic tumor models was broadly classified into 3 categories: highly responsive (ie, complete and durable tumor regressions were observed), partially responsive (ie, tumor growth inhibition was observed), and intrinsically resistant to therapy. Gene and protein expression signatures revealed that the more responsive models expressed higher levels of both PD-1 ligand (PD-L1) and tumor-infiltrating lymphocytes compared with nonresponsive models. To further evaluate mechanisms that could potentially enhance the antitumor activity of anti-PD-1 in these tumor models, muDX400 was combined with a number of different chemotherapies, targeted therapies, and other immunotherapies. Because immune suppression is a common side effect associated with many standard-of-care therapies, we evaluated the potential abrogation of muDX400-mediated antitumor activity when combined with approved therapies by scheduling the dosing regimen to examine concurrent and sequential administration of these agents. In the models in which enhanced antitumor activity was evident, we evaluated the immune landscape of blood, tumors, and draining lymph nodes by immuno-phenotyping and molecular profiling. These data provide preclinical support to expand the clinical development of pembrolizumab into additional cancer types as both a single agent and in combination with other approved anticancer therapies. Additional studies with muDX400 are ongoing to further elucidate the mechanism of action of PD-1 blockade and to better understand the antitumor responses observed in clinical trials of pembrolizumab. Citation Format: Elaine M. Pinheiro, Ruban Mangadu, Uyen T. Phan, Mingmei Cai, Yanhong Ma, Heather A. Hirsch, Terrill K. McClanahan, Raymond J. Moniz, Ali-Samer Al-Assaad, Samik Basu, Yaolin Wang, Venkataraman Sriram, Joseph H. Phillips, Brian J. Long. Evaluation of the antitumor activity of anti-PD-1 immunotherapy as a single agent and in combination with approved agents in preclinical tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 269. doi:10.1158/1538-7445.AM2015-269