Background: Human Immune-reconstituted Mice, generated by transplanting pre-validated human CD34+ hematopoietic stem cells (HSC) into immune-compromised mice, are extremely useful in basic and applied human disease research. Many cancer therapies, including immune checkpoint inhibitors such as the anti-PD-1 monoclonal antibody, rely on an intact immune system to release immunosuppression and destroy cancer cells.

Material and methods: We evaluated the effects of anti-PD-1 in humanized mice in donor cohorts utilizing the cancer matrix of 5 HSC donor cohorts of humanized animals with PDX models from 7 small cell lung cancer (SCLC). We also tested anti-PD-1 in 1 triple negative breast cancer (TNBC) model and in 1 MDA-MB-231 study.

Results: Here, we show that HSC derived human immune cell engraftment does not have significant effects on patient derived xenograft (PDX) tumor growth. However, humanization is required for anti-tumor response to anti-PD-1. In MDA-MB-231 study, tumors showed complete regression after the first round of treatment. Re-engraftment of same animals with MDA-MB-231 cells showed minor tumor growth before complete regression again. Aged match control naïve animals engrafted with same cells showed normal tumor growth. In SCLC studies anti-PD-1 efficacy varied between the models, which clearly underscores the inherent donor to donor variability in this humanized model system. Tumors from these studies were then analyzed to determine target engagement of anti-PD-1, tumor infiltrating lymphocytes (TILs) characterization and histology comparing anti-PD-1 responders vs non-responders. As expected, in this study, we demonstrate humanization of the animals is necessary to evaluate the efficacy of anti-PD-1 therapy and can elicit an immunotherapy mediated anti-tumor effect.

Conclusion: Here we demonstrate the development of humanized mouse studies with ability to run multi point analysis to determine the outcome of treatment.

Citation Format: Hooman Izadi, Tommy Broudy, Deborah Yan, Jayant Thatte. Evaluation of efficacy and immune response to PD1 checkpoint inhibition in human immune-reconstituted mice using patient-derived xenograft 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 4707. doi:10.1158/1538-7445.AM2017-4707