Novel Immunotherapeutic Activity Of Jak And P13k Delta Inhibitors In A Model Of Pancreatic Cancer

Immunotherapeutic agents are emerging as key components of efficacious multi-agent regimens in cancer. The majority of immunotherapeutic agents developed thus far either attempt to stimulate a more productive anti-tumoral immune response or to inhibit key proteins in the immunosuppressive tumoral milieu. In contrast, agents targeting signal transduction molecules have been largely developed for their ability to impact the proliferative potential of tumor cells directly. Notably, the JAK/STAT and PI3Kδ signaling pathways have been shown to contribute not only to tumor cell proliferation and survival but also to play a crucial role in regulating stromal cells, including immune cells, which are recruited to the tumor microenvironment. Activation of these pathways has been shown to result in the recruitment and expansion of predominantly negative regulatory cells such as myeloid derived suppressor cells and regulatory T cells, suggesting that inhibition of JAK/STAT and PI3Kδ signaling may promote antitumor immunity. Therefore, we have examined the immunotherapeutic potential of selective inhibitors of either JAK or PI3Kδ. We demonstrate that inhibitors of either JAK or PI3Kδ block tumor growth as single agents in the immuno-competent syngeneic PAN02 pancreatic model, which is not driven by oncogenic JAK or PI3K signaling. Tumor growth inhibition is not observed in immunocompromised mice, demonstrating that the anti-tumor effects of these agents require an intact immune system. These agents were tested pairwise with each other and in combination with other immune checkpoint modulators, including an anti-PD-L1 antibody and the IDO1 inhibitor INCB24360. The combinations of JAK inhibition with IDO1 inhibition, PI3Kδ inhibition or PD-1/PD-L1 blockade resulted in enhanced efficacy. Mechanistic studies revealed that the combination of JAK and IDO1 inhibition did not alter the number of infiltrating T cells within the tumor, but instead resulted in a more activated phenotype of the infiltrating T cells, leading to higher levels of IFNγ production. In contrast, combination treatment with regimens that included an inhibitor to PI3Kδ led to a marked increase in the numbers of T cell infiltrates, although the cells were not maximally activated. Further studies to understand the complex cellular responses elicited by these inhibitors may provide the mechanistic rationale to explore JAK or PI3Kδ inhibitor-based immunotherapy combinations in the clinic. Citation Format: Holly K. Koblish, Michael Hansbury, Liang-Chuan S. Wang, Gengjie Yang, Taisheng Huang, Chu-Biao Xue, Yun-Long Li, Eddy Yue, Andrew Combs, Wenqing Yao, Reid Huber, Peggy Scherle. Novel immunotherapeutic activity of JAK and PI3Kδ inhibitors in a model of pancreatic cancer. [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 1336. doi:10.1158/1538-7445.AM2015-1336