Background Despite transforming effects of immune checkpoint blockade (ICB) therapy, objective response rates are low for most solid tumors. In the tumor microenvironment (TME), regulatory T cells are functionally unstable, likely due to changes in Treg metabolism seen in the tumor milieu. Destabilized Treg are susceptible to reprogramming wherein they can be induced to lose their immunosuppressive function and to secrete interferon-gamma (IFN-g). Thus, Treg reprogramming offers a novel strategy to sensitize unresponsive tumors to ICB. Notably, blockade of MALT1 protease induces Treg reprogramming in the TME but without affecting Treg in healthy tissue. MPT-0118, an orally dosed MALT1 inhibitor, was developed to reprogram Treg in the TME and is currently being assessed in patients with advanced tumors. Approach Treatments included MPT-0118 and anti-PD-1. In vivo studies in mice assessed anti-tumor effects using D4M.3A, B16F10, and MC38 syngeneic tumors. Human and mouse tumor tissues were evaluated for Treg reprogramming by in situ hybridization or flow cytometry. Studies in rats and dogs assessed pharmacokinetics and safety. Results MPT-0118 demonstrated dose-dependent in vivo anti-tumor activity. Consistent with the hypothesis that Treg reprogramming supports anti-tumor immunity by initiating IFN-g-driven tumor inflammation, the effect was strongest in combination with anti-PD-1 and in models that are not responsive to ICB alone. MPT-0118-treated tumors showed an increase in IFN-g-secreting Treg, associated with decelerated tumor growth. Ex vivo, MPT-0118 induced Treg reprogramming in tumors resected from patients with colorectal and endometrial cancers. While MPT-0118 caused Treg to produce IFN-g, no changes in the frequencies of Treg circulating in blood were detected in rats. Modeling of the human effective dose and toxicology studies demonstrate a >2x therapeutic window in patients. Conclusions MPT-0118 Treg reprogramming represents a novel strategy with the potential to improve responses to ICB therapy in solid tumors. A Phase 1/1b dose-escalation and cohort-expansion clinical trial evaluating MPT-0018 is underway.

Citation Format: Peter Keller, Irina Mazo, Yun Gao, Vijayapal Reddy, Francisco Caballero, Sam Kazer, Dannah Miller, Roberto Gianani, James E. Marvin, Bret Stephens, Gregory L. Beatty, Ulrich H. von Andrian, Thorsten R. Mempel. Reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P106.