Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor

• Published in: Journal for immunotherapy of cancer Vol. 9; no. 1; p. e001402
• Main Authors: You, Dan, Hillerman, Stephen, Locke, Gregory, Chaudhry, Charu, Stromko, Caitlyn, Murtaza, Anwar, Fan, Yi, Koenitzer, Jennifer, Chen, Yali, Briceno, Stephanie, Bhadra, Rajarshi, Duperret, Elizabeth, Gullo-Brown, Johnni, Gao, Chan, Zhao, Dandan, Feder, John, Curtin, Joshua, Degnan, Andrew P, Kumi, Godwin, Wittman, Mark, Johnson, Benjamin M, Parrish, Karen E, Gokulrangan, Giridharan, Morrison, John, Quigley, Michael, Hunt, John T, Salter-Cid, Luisa, Lees, Emma, Sanjuan, Miguel A, Liu, Jinqi
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.01.2021; BMJ Publishing Group
• Series: Original research
• Subjects: Adenosine; Animals; Antigens; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Basic Tumor Immunology; Biological products; Bone Neoplasms - drug therapy; Bone Neoplasms - immunology; Bone Neoplasms - metabolism; Cancer; Cancer therapies; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytomegalovirus; Gene Expression Regulation, Neoplastic - drug effects; Ginsenosides - administration & dosage; Ginsenosides - pharmacology; Human papillomavirus; Humans; Immune system; Immunotherapy; Kinases; Laboratory animals; Lymphocytes; Mice; Peptides; Protein Serine-Threonine Kinases - antagonists & inhibitors; Proteins; Receptors, Antigen, T-Cell - metabolism; Sarcoma - drug therapy; Sarcoma - immunology; Sarcoma - metabolism; Signal transduction; T cell receptors; Treatment Outcome; Tumor Microenvironment - drug effects; Tumor necrosis factor-TNF; Tumors; Xenograft Model Antitumor Assays; California; United States > US; Massachusetts; Wisconsin; New Jersey; CD8-positive T-Lymphocytes; dendritic cells; lymphocytes; tumor microenvironment; tumor-Infiltrating; adaptive Immunity
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-001402

BackgroundHematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy.MethodsHuman primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo.ResultsCompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease.ConclusionCompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.