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Immune checkpoint blockade is effective for a subset of patients across many cancers, but most patients are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatase PTPN2 is a central regulator of inflammation, and genetic deletion of PTPN2 on either tumour cells or host immune cells promotes anti-tumour immunity. However, inhibitors of PTPN2 with suitable pharmacokinetic properties for oral administration have not been described. Here, we present the characterization of ABBV-CLS-484 (A484), a potent active site inhibitor of PTPN2 and the closely related phosphatase PTPN1. A484 treatment in vitro amplifies the response to interferon gamma, and monotherapy A484 treatment generates robust anti-tumour immunity in several murine cancer models. Through in vivo studies and single cell transcriptional profiling of tumour-infiltrating lymphocytes (TIL) from A484-treated mice, we show that A484 inflames the tumour microenvironment and promotes CD8+ T cell function by enhancing cytokine signaling and decreasing T cell exhaustion and dysfunction. Our results demonstrate that oral administration of small molecule inhibitors of PTPN2/N1 can induce potent anti-tumour immunity in mouse models. PTPN2/N1 inhibitors offer a promising new strategy for cancer immunotherapy and are currently being evaluated clinically in patients with advanced solid tumours (NCT04777994). More broadly, our study shows that small molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to current antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge A484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics targeting this important class of enzymes. Citation Format: Hakimeh Ebrahimi-Nik, Arvin Iracheta-Vellve, Kira E. Olander, Thomas R.G. Davis, Sarah Y. Kim, Mitchell D. Yeary, James C. Patti, Tyler M. Balon, Omar Ismail Avila, Cun Lan Chuong, Meng-Ju Wu, Christina K. Baumgartner, Keith M. Hamel, Kathleen A. McGuire, Rebecca Mathew, Carey Backus, Ian C. Kohnle, Zhaoming Xiong, Elliot P. Farney, Jennifer M. Frost, Geoff T. Halvorsen, Matthew Rees, Andrew Boghossian, Melissa Ronan, Jennifer A. Roth, Todd R. Golub, Gabriel K. Griffin, Nabeel El-Bardeesy, Clay C. Beauregard, Philip R. Kym, Kathleen B. Yates, Robert T. Manguso. Small molecule inhibition of PTPN2/1 inflames the tumour microenvironment and unleashes potent CD8+ T cell immunity [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A41. |
