Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT).


We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to investigate its pharmacokinetic properties and antitumor effects in several murine tumor models as well as patient-derived organotypic tumor spheroids (PDOTS). Results: (S)-mepazine demonstrated significant antitumor effects and was synergistic with anti-PD-1 therapy in vivo and ex vivo but did not affect circulating Treg frequencies in healthy rats at effective doses. Pharmacokinetic profiling revealed favorable drug accumulation in tumors to concentrations that effectively blocked MALT1 activity, potentially explaining preferential effects on tumor-infiltrating over systemic Tregs.


The MALT1 inhibitor (S)-mepazine showed single-agent anticancer activity and presents a promising opportunity for combination with PD-1 pathway-targeted ICT. Activity in syngeneic tumor models and human PDOTS was likely mediated by induction of tumor-associated Treg fragility. This translational study supports ongoing clinical investigations ( Identifier: NCT04859777) of MPT-0118, (S)-mepazine succinate, in patients with advanced or metastatic treatment-refractory solid tumors.

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Author notes

Source of Support: This study received funding from Monopteros Therapeutics, Inc. The funder was involved in study design; collection, analysis, and interpretation of data; and writing of this article and the decision to submit it for publication.

Competing Interests

Conflicts of Interest: Mauro Di Pilato, Yun Gao, Irina Mazo, Samuel W. Kazer, and Kevin Litchfield are consultants for Monopteros Therapeutics. Outside of the submitted work, Kevin Litchfield has a patent pending on indel burden and CPI response; he has received speaker fees from Roche tissue diagnostics and research funding from CRUK TDL/Ono/LifeArc alliance and Genesis Therapeutics. Ulrich H. von Andrian and Thorsten R. Mempel are cofounders and shareholders of Monopteros Therapeutics. Russell W. Jenkins has received research support from Monopteros Therapeutics and is on the advisory board for and has a financial interest in XSphera Biosciences; his interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. Daniel Krappmann is an advisor to and has received research support from Monopteros Therapeutics. Peter Keller is an employee and shareholder of Monopteros Therapeutics. The remaining authors have no disclosures. The views expressed in this article are those of the authors and not an official position of Monopteros Therapeutics, Inc.

This work is published under a CC-BY-NC-ND 4.0 International License.

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