PTX-35, a potential first-in-class TNFRSF25 agonist, reduced the suppressive activity of regulatory T cells and enhanced CD4+T cell effector responses, in the presence of tumor antigens, in a murine melanoma model.

Abstract Tumor cells evolve multiple mechanisms to escape immune surveillance, one of which is to establish a tolerogenic microenvironment by recruiting immune suppressive cell types such as regulatory T cells (Tregs). Tumor Necrosis Factor Receptor Super Family 25 (TNFRSF25), also known as Death Receptor 3 (DR3), is a potent costimulatory molecule and is preferentially expressed by activated and antigen-experienced T cells. PTX-35, a potential first-in-class TNFRSF25 agonist antibody, is currently in a Phase 1 clinical trial in patients with solid tumors. The purpose of this study was to characterize the impact of mouse PTX-35 (mPTX-35) on tumor growth as well as Treg stability and functionality, including propensity of Tregs to be converted to effector CD4+ T cell subtypes. In this murine melanoma model, C57BL/6 mice were subcutaneously injected with B16.F10-OVA tumor cells. Mice were administered various combinations of mPTX-35, a PD-1 inhibitor, and tumor antigens. When mPTX-35 was administered with tumor antigens, we observed: (1) reduction in the suppressive activity of Tregs, as reflected by decreased expression of CD25 and Nrp1 among Tregs in the peripheral blood and CTLA-4 in the tumor; (2) compromised Treg stability and increased Treg plasticity, including an increased percentage of RORγt+Foxp3+ unstable Tregs and increased conversion of Tregs to RORγt+Foxp3- Th17 cells; (3) increased effector IFNγ+ Th1 cells and effector IL17+ Th17 cells in blood and tumor microenvironment; and (4) elevation in effector IFNγ+ CD8+ T cells in the blood. Importantly, these changes in Treg stability and functionality were associated with delayed tumor progression. In conclusion, we demonstrate that mPTX-35, in the presence of tumor antigens, resulted in the reprogramming of the Treg cell phenotype, including reduced suppressive activity of Tregs and increased plasticity towards inflammatory Th1 and Th17 cells. PTX-35 has the potential to improve the efficacy of treatment regimens where tumor antigens are released. Citation Format: Khalid W. Kalim, Vikas Tahiliani, Jayalakshmi Miriyala, Patrick J. Dillon, Anh M. Trinh, Abra N. Chaney, Matthew M. Seavey, Eric P. Dixon, Rahul R. Jasuja, Jeff T. Hutchins. PTX-35, a potential first-in-class TNFRSF25 agonist, reduced the suppressive activity of regulatory T cells and enhanced CD4+ T cell effector responses, in the presence of tumor antigens, in a murine melanoma model [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 604.