Abstract 3517: Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor activity

Abstract

Abstract Hematopoietic progenitor kinase 1 (HPK1, mitogen-activated kinase kinase kinase kinase 1 [MAP4K1]), a cytosolic STE20 ser/thr kinase from the germinal center family of kinases, regulates the function of diverse immune populations including T cells, B cells, and dendritic cells. In T cells, activated HPK1 regulates T cell receptor (TCR) signaling by phosphorylating the adaptor protein SLP76 on Ser376, which induces the association of SLP76 with 14-3-3 proteins. This SLP76/14-3-3 complex leads to its disassociation from the TCR signalosome, resulting in reduced downstream TCR signaling. The kinase activity of HPK1 is necessary for its regulatory function as mice expressing a mutant kinase-inactive HPK1 demonstrate enhanced T cell activity and superior tumor growth control compared to their WT counterparts. Here we describe a highly potent, selective and orally bioavailable small molecule inhibitor of HPK1 which displays sub-nanomolar HPK1 inhibition, good selectivity against MAP4K family members and oral bioavailability in preclinical animal models. Pharmacological inhibition of HPK1 kinase activity with Gilead’s HPK1 inhibitor compound demonstrates robust inhibition of pSLP76 S376 with concomitant enhancement in T cell activation, proliferation and effector function in in vitro assays. These immune enhancing effects translate into in vivo preclinical tumor models, where treatment with Gilead’s HPK1 inhibitor compound results in heightened T cell activation and effector function and enhanced tumor growth control both as a single agent and in combination with PD-1 blockade. In summary, our data show that Gilead’s HPK1 inhibitor compound is expected to be a selective, orally bioavailable HPK1 inhibitor with potential to combine with checkpoint inhibitors and other immuno-oncology agents. Citation Format: Jacob S. Lee, Pamela Toy, Gundula Min-Oo, Tony Lee, Patrick Salvo, JeanPhilippe Belzile, Sheila Clancy, Jonathan Nazareno, Mengshu Xu, Weimei Xing, Marilyn Giacomini, Rex Santos, Lance Stapleton, Adele Wang, Vladislava Juric, Scott A. Mitchell, Michelle Kuhne. Pharmacologic inhibition of HPK1 kinase activity enhances immune cell activation and T cell mediated anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3517.