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Abstract Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune cells and suppresses the immune function of a wide range of cells, including T cells, B cells, and dendritic cells (DCs). Recent studies have shown that HPK1 is correlated with increased T cell exhaustion, one of hallmark phenomena for acquired resistance to immune checkpoint inhibitors (ICIs), that is a major obstacle in the current immunotherapy regimen with an increasing need of novel agent to overcome it. We have discovered FB849, a highly potent, highly selective, and orally available HPK1 inhibitor especially with an excellent selectivity over key immune-related off target kinases. FB849 confers the activation of various human primary immune cells such as T cells, B cells, and DCs in vitro. FB849 elicited robust anti-cancer efficacy in syngeneic mouse models including MC38 and CT26 both as a monotherapy and in combination with a PD-1 antagonist. A dramatic synergistic efficacy with FB849 and PD-1 combination was observed in EMT6. Durable effects possibly through immunological memory were also confirmed in CT26. Under a CD8+ T cell depletion condition in vivo, FB849 still maintained monotherapy efficacy, demonstrating its anti-cancer immunity through CD8+ T cell-independent pathway possibly via efficacy through myeloid lineage. FB849 significantly reduced the LAG3+ and PD-1+ exhausted T cells and CD25+ FoxP3+ regulatory T cells, simultaneously depleted tumor associated macrophages (TAMs), and modulated dendritic cell population in the syngeneic tumors. To better understand how FB849’s effects on human cancer, FB849 was evaluated in isolated TILs (tumor-infiltrating lymphocytes) from patients with renal cell carcinoma and other cancer types. CD8+ T cells from a RCC patient was highly activated evidenced by the increased cell proliferation and the enhanced cytokine secretion by ex vivo treatment of FB849 alone or by the combination with PD-1 antagonist. Similar phenomena were observed in gastric cancer, hepatocellular carcinoma, colorectal cancer, and head and neck cancer. FB849 treatment resulted in the activation of not only stem-like T cells but also in the partial reinvigoration of terminally differentiated T cells from a RCC patient. These data from patient TIL’s together with mouse TIL’s pinpoint unprecedented anti-tumor mechanism by FB849 through modulation of exhausted T cells as well as myeloid cells. Altogether, this study supports the planned clinical development of FB849 as a promising immuno-oncology agent as a monotherapy in the selected cancer types and as post-ICI combination with a PD-1 antagonist. Citation Format: Hyekyoung Kim, Seungmook Lim, A Yeong Park, Jinhwa Lee, Jamie Jae Eun Kim, Seung Hyuck Jeon, Yong Joon Lee, Eui-Cheol Shin, Seongkon Kim. A selective HPK1 inhibitor FB849 reprograms intratumoral immune cells and elicits strong anti-cancer immunity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2651.
Kim et al. (Fri,) studied this question.