Abstract 1657: Evaluating anti-tumor activity of the human anti-PD-1 antibody pembrolizumab using humanized mouse models

Autor: Razvan Cristescu, Kallol Ray, Jennifer H. Yearley, Douglas Linn, Brian Long, Shuli Zhang, Sripriya Dhandapani, Sarav Kaliyaperumal
Rok vydání: 2017
Předmět:
Zdroj: Cancer Research. 77:1657-1657
ISSN: 1538-7445
0008-5472
Popis: Targeting immune checkpoints has proven to be an effective strategy for reactivating the immune system to elicit potent anti-tumor activity. For example, the anti-PD-1 antibody pembrolizumab has shown robust and durable clinical activity in numerous malignancies including melanoma and non-small cell lung cancer. Unfortunately, a subset of patients do not benefit from pembrolizumab treatment. Ongoing molecular analyses of patient samples are establishing gene signatures which aim to more accurately predict which patients will benefit from immunotherapy. However, there are currently no preclinical in vivo platforms that comprehensively translate these clinical findings. Therefore, we have explored the use of mice engineered with a human immune system to examine the anti-tumor activity of pembrolizumab against a panel of human tumor xenografts derived from both cultured cell lines as well as patient tissue. Tumor models were selected based on parameters including PD-L1 expression and mutational load in order to closely mimic responder patients in the ongoing pembrolizumab clinical trials. Our data confirm that pembrolizumab can induce significant anti-tumor efficacy in humanized mice inoculated with human tumor models derived from both cancer cell lines and patient tumors. In responsive models, pembrolizumab caused significant tumor growth inhibition and, in some instances, tumor regressions. FACS analyses confirmed effective targeting of PD-1+ T cell populations. Anti-tumor efficacy correlated with increased effector T cell to regulatory T cell ratios as well as an elevated T cell infiltrate presence. Nonresponsive models lacked robust immune infiltration detectable by FACS or IHC, consistent with clinical data. Furthermore, presence of cytolytic activity at baseline and T-cell inflamed environment were evaluated using transcriptome analysis and subsequently linked to pembrolizumab response and to somatic neoantigen burden of the tumors. Together these studies validate the utility of humanized mice in the preclinical development of novel cancer immunotherapies and may also be beneficial in better defining the patient responder hypothesis and its prognostic value. Additionally, humanized mice may help identify optimal combination treatment regimens to provide more meaningful clinical benefit to patients who do not respond to single-agent therapy with pembrolizumab. Citation Format: Douglas E. Linn, Razvan Cristescu, Kallol Ray, Shuli Zhang, Sripriya Dhandapani, Sarav Kaliyaperumal, Jennifer H. Yearley, Brian J. Long. Evaluating anti-tumor activity of the human anti-PD-1 antibody pembrolizumab using humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1657. doi:10.1158/1538-7445.AM2017-1657
Databáze: OpenAIRE
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