Abstract 1020P
Background
Despite transforming effects of immune checkpoint therapy (ICT), objective response rates are low in solid tumors. In the tumor microenvironment (TME), regulatory T-cells (Treg) are unstable, likely due to changes in Treg metabolism in the tumor milieu. Destabilized Treg can be reprogrammed to lose their immunosuppressive function and secrete IFN-γ, offering a strategy to sensitize unresponsive tumors to ICT. Blockade of MALT1 protease induces Treg reprogramming in the TME without affecting Treg in healthy tissue. MPT-0118, an orally-dosed MALT1 inhibitor, was developed to reprogram Treg and is currently assessed in patients with advanced tumors.
Methods
Test articles were MPT-0118 and anti-PD-1. In vivo studies in mice assessed anti-tumor effects using D4M.3A, B16F10, and MC38 syngeneic tumors. Studies in rats and dogs assessed pharmacokinetics and safety. Tumor tissues were evaluated for Treg reprogramming by histological imaging and flow cytometry. Murine- and patient-derived organotypic tumor spheroids (MDOTS and PDOTS) were used to determine immune-mediated cell killing ex vivo.
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-γ-driven tumor inflammation, the effect was strongest in combination with anti-PD-1 and in models that are not responsive to ICT alone. MPT-0118-treated tumors showed an increase in IFN-γ-secreting Treg, associated with decelerated tumor growth. Ex vivo, MPT-0118 reduced cell viability in D4M.3A MDOTS and colorectal cancer PDOTS in a dose-dependent manner at concentrations also achieved in tumors following in vivo dosing. While MPT-0118 induced Treg reprogramming in tumors, 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 mitigate the critical problem of low ICT response rates in solid tumors. MPT-0118 recently started a phase 1/1b dose-escalation and cohort-expansion clinical trial.
Clinical trial identification
NCT04859777.
Editorial acknowledgement
Legal entity responsible for the study
Monopteros Therapeutics Inc.
Funding
Monopteros Therapeutics Inc.
Disclosure
P. Keller: Financial Interests, Personal, Full or part-time Employment: Monopteros Therapeutics; Non-Financial Interests, Personal, Leadership Role: Divide and Conquer. I. Mazo: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. Y. Gao: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. V. Reddy: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. F. Caballero: Financial Interests, Advisory Role: Monopteros Therapeutics. B. Stephens: Financial Interests, Institutional, Research Grant: Monopteros Therapeutics. R.W. Jenkins: Financial Interests, Personal, Stocks/Shares: Xsphera Bio; Financial Interests, Institutional, Research Grant: Monopteros Therapeutics. U.H. von Andrian: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. T.R. Mempel: Financial Interests, Personal, Stocks/Shares: Monopteros Therapeutics. All other authors have declared no conflicts of interest.