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 in 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. Using a multifaceted approach, tumors from these models were extensively characterized at the molecular and cellular level by gene expression profiling, whole exome sequencing, fluorescence-activated cell sorting, and immunohistochemistry to help elucidate mechanisms of action and biology associated with response and resistance to anti-PD1 treatment. Analyses included but were not limited to the evaluation of mutational burden, immune cell activation and migration, interferon signaling, antigen presentation (major histocompatibility [MHC] class I and II), and expression of novel targets.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. In the models in which enhanced antitumor activity was evident, we evaluated the immune landscape of blood, tumors, and draining lymph nodes by 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: Heather Hirsch, Ruban Mangadu, Mingmei Cai, Yanhong Ma, Uyen Phan, Yaolin Wang, Venkataraman Sriram, Joseph H. Phillips, Terri McClanahan, Brian Long, Elaine M. Pinheiro. Evaluation of the antitumor activity and molecular characterization of mouse syngeneic tumor models in response to anti-PD-1 treatment as a single agent and in combination with approved agents. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B114.
- ©2016 American Association for Cancer Research.