In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1717-1717
Abstract:
Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a serine/threonine kinase that has been demonstrated to have suppressive effects across a range of immune cells, including T cells and dendritic cells. Loss of MAP4K1 kinase activity is sufficient to enhance T cell receptor (TCR) signaling resulting in robust anti-tumor immunity alone and in combination with checkpoint inhibition. These data support that MAP4K1 is a novel and attractive target for cancer immunotherapy. We have designed a series of potent, selective, and orally bioavailable inhibitors of MAP4K1. Treatment of primary human T cells or peripheral blood with either BLU2069 or BLU6348 was able to inhibit phosphorylation of pSLP76, a scaffolding protein that regulates MAPK downstream of the TCR. In addition, we show that compound treatment can enhance cytokine secretion and proliferation in human T cells in response to TCR crosslinking. The therapeutic benefit of MAP4K1 inhibition alone and in combination with anti-PD-L1 was evaluated in multiple syngeneic mouse tumor models including MCA205, MC38 and EMT-6. Treatment with either compound alone led to a reduction in tumor growth that was further enhanced when combined with anti-PD-L1 therapy. When tumors were grown in immunocompromised mice (MCA-205) or in the setting of CD8+ T cell depletion (MC-38), the anti-tumor effect of BLU2069 and BLU6348 respectively was lost, confirming the importance of immune cells in compound mediated antitumor effects. We further show that MCA205 tumors harvested from mice treated with BLU2069 had increased intratumoral CD8+ T cell infiltration, resulting in enhanced CD8/Treg ratios. In addition, transcriptional analysis of tumor lysates showed that BLU2069 significantly increased genes associated with an effector phenotype. These data support that pharmacological inhibition of MAP4K1 reduced tumor burden and enhanced antitumor immunity in preclinical tumor models. Finally, we show that MAP4K1 inhibition can enhance CD3/CD28-induced IL2 and IFNγ in human tumor infiltrating lymphocytes (TILs) generated from melanoma or non-small cell lung cancer (NSCLC) primary tumors. This work describes the identification of potent small molecule inhibitors of MAP4K1 which could be novel therapeutic agents and induce an effective immune response either alone or in combination with approved checkpoint inhibitors. Citation Format: Kerrie Faia, Alberto Toso, Kristina Fetalvero, Marly Roche, Steven Bench, Erin O'Hearn, Qiongfang Cao, Kerry-Ann Bright, Debora Paduraru, Andrea Romagnani, Weifan Weng, Tina Zimmermann, Michael Burke, Joshua Close, Luke Green, Joseph Kim, Chandra Miduturu, Alison Ribeiro, Marina Bacac, Sylvia Herter, Emanuele Perola, Michael Sheets, Jan Eckmann, Gordon Heidkamp, Tary Traore, Erik Gerson, Rich Woessner, Carsten Wolter, Felix Scheuplein, Nisha Perez, Timothy LaBranche, Grace Silva, Chaoyang Ye, Caitlin Utt, Stefan Gross, James R. Bischoff, Marion Dorsch, Tim Guzi, Klaus Hoeflich, Jason Brubaker. MAP4K1 inhibition enhances immune cell activation and anti-tumor immunity in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1717.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2021-1717
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink
