Abstract 2162: A potent and highly selective HPK1 inhibitor as a combination strategy to improve the clinical response of the immune checkpoint inhibitor

Combining the HPK1 inhibitor with the anti-PD-1 antibody has demonstrated clinical benefit by restoring suppressed immune response. Here, we present our novel HPK1 inhibitor IN-122517 exhibiting good HPK1 inhibition potency and selectivity against 468 kinases including immune-related off-target kinases. Consistently, it potently reduced SLP76 phosphorylation and induced IL-2 production in human peripheral blood mononuclear cells (PBMCs). Preclinical studies have shown beneficial tumor response to IN-122517 as a monotherapy and also improved efficacy when combined with anti-PD-1 monoclonal therapy. In the combination group, complete responses (CRs) were observed in a subset of animals, and re-challenge experiments confirmed the absence of tumor regrowth, indicating the establishment of an immune memory response. Tumor-infiltrating lymphocytes showed increased infiltration of T cells, natural killer (NK) cells, and dendritic cells (DCs), demonstrating the compound's potency in activating and recruiting immune effectors within the tumor microenvironment (TME). These data supported the nomination of IN-122517 into IND-enabling studies as a combination partner with Immune checkpoint inhibitors (ICIs). Citation Format: Joonseok Byun, Jong Hyun Lee, Seungjin Jo, Doyoung Kim, Hyunwoo Shin, Jong Ryoul Choi, Seunghee Ji, Hye-Jung Kim, Donghyun Kim, Bong Tae Kim. A potent and highly selective HPK1 inhibitor as a combination strategy to improve the clinical response of the immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2162.