HDAC and PD-1 inhibition in humanized triple-negative breast cancer xenografts.

Abstract

e14604 Background: There is great interest in investigating immune checkpoint inhibition in combination with novel agents, however, preclinical studies are limited by the lack of immune-competent human cancer cell line xenograft models. We developed a “hematopoietic” humanized mouse model to address this unmet need. HDAC inhibitors (HDACi) induce T-cell chemokine expression and enhance response to PD1 inhibitors in lung cancer models. We evaluated the combination of OKI-179, a novel Class I HDACi and nivolumab in our humanized mouse model. Methods: BRGS newborn pups were transplanted with CD34+ cells purified from umbilical cord blood. At 16 weeks, MDA-MB-231 cells were implanted in the flanks of the mice. When the average tumor size reached ~150-300 mm3, the mice were randomized into vehicle, nivolumab, OKI-179, or the combination treatment according to % chimerism. At the end of the treatment, mice were euthanized and tissues were collected for further analysis. Results: We observed a statistically significant improvement in tumor growth inhibition with the combination of OKI-179 and nivolumab (%TGI = 77%) as compared to single agent nivolumab (45%TGI). Nivolumab treatment led to a significant decrease in PD-1 expression on T cells. We also observed an increased number of TILs (CD8+ T cells) and T cells in the lymph nodes of treated mice suggesting T cell expansion. All mice were highly chimeric and responding tumors exhibited an increase in CD44 high IFN+ T cells. We observed a higher CD8% and a higher effector memory % (HLADR+, CD45RO+) in these mice. Conclusions: We successfully established a humanized TNBC human cancer cell line xenograft model, with tumor engraftment occurred in all humanized mice. Mice treated with nivolumab demonstrating the development of lymph nodes that were populated by activated T cells. The combo resulted in superior tumor growth inhibition. These preliminary results demonstrate that human immunity and PD-1 expressing T cells exist in these models and provide the basis for planned immunotherapy combination studies.