Abstract 1328: Molecular characterization of mouse syngeneic tumor models in response to treatment with anti-PD-1 immunotherapy
Authors: Hirsch Heather A. , Pinheiro Elaine M. , Cai Mingmei , Ma Yanhong , Sathe Manjiri , Ayers Mark , McClanahan Terrill K. 
Published: August 2015

Although there are a variety of immune cells localized in the tumor microenvironment, they are generally present in a quiescent state. The goal of cancer immunotherapy is to activate immune effector cells in the tumor microenvironment to recognize tumor cells and elicit an immune response that results in elimination of the tumor. Checkpoint inhibitors and activators that target T-cell receptors provide attractive targets for cancer immunotherapies by either enhancing T-cell activation pathways or inhibiting T-cell checkpoint/anergy pathways. In 2014, the anti-programmed death receptor 1 (PD-1) antibody pembrolizumab (MK-3475) was approved for use in patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600 mutation positive, a BRAF inhibitor. Pembrolizumab is currently being explored in multiple clinical trials covering ∼30 different cancer types. A more complete understanding of the mechanism of action and biology associated with both response and resistance to pembrolizumab is critical to better inform future clinical development and to provide insight into the development of additional immuno-oncology therapies.

Preclinical mouse syngeneic tumor models have been used extensively to support the clinical development of drugs such as pembrolizumab and to help identify novel targets that have the potential to synergize with anti-PD-1 therapies. We employed a panel of mouse syngeneic tumor models that have been used to assess the efficacy of muDX400, a fully murinized surrogate antibody of pembrolizumab. Tumors from these models were extensively characterized at the molecular and cellular levels at baseline and after muDX400 treatment. Data obtained from multiple experimental sources, including RNA expression, DNA mutation and copy number, fluorescence-activated cell sorting, and immunohistochemistry, have been integrated to inform pembrolizumab mechanisms of action and resistance, pharmacodynamic biomarkers, responder identification, and indication selection. These findings are also being compared to data being obtained from ongoing clinical trials of pembrolizumab to help better understand whether these preclinical models can be translated to the clinic. These preclinical syngeneic tumor models also provide the opportunity to formulate and test specific hypotheses to more completely understand the biology behind the clinical successes currently observed with novel cancer immunotherapies, including anti-PD-1 antibodies such as pembrolizumab. The hypotheses under evaluation include mutational burden, immune cell activation and migration, interferon signaling, antigen presentation (MHC class I and II), and expression of novel targets that will help lead to the development of the next generation of cancer immunotherapies.

Citation Format: Heather A. Hirsch, Elaine M. Pinheiro, Mingmei Cai, Yanhong Ma, Manjiri Sathe, Mark Ayers, Terrill K. McClanahan. Molecular characterization of mouse syngeneic tumor models in response to treatment with anti-PD-1 immunotherapy. [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 1328. doi:10.1158/1538-7445.AM2015-1328