Abstract 4724: Immuno-modulatory activity of BPM31510 supports T cell viability, proliferation, and function while reversing early signs of exhaustion
Authors: Nastke Maria , Kazerounian Shiva , Gaur Nidhi , Jayashankar Shyamali , Linsenmayer David , Spencer Carrie , Nambiar Arun , Sarma Aishwarya , Diers Anne R. , Gesta Stephane , Vishnudas Vivek , Sukhatme Vikas P. , Narain Niven R. , Sarangarajan Rangaprasad 
Published: August 2018

Abstract
Regulation of mitochondrial metabolism is crucial to alter immune cell differentiation and function; therefore, therapeutic agents which regulate mitochondrial metabolism may have efficacy in immune-mediated tumor elimination. BPM31510 is a clinical stage, nanodispersion of ubidecarenone (coenzyme Q10), an electron transfer molecule in the mitochondrial electron transport chain required for oxidative phosphorylation. Here, we used BPM31510 to assess the role of CoQ10 in the regulation of T cell function. Healthy donor peripheral blood mononuclear cells (PBMCs) activated ex vivo with αCD3/CD28 beads were used as model system to test the effects of BPM31510 on viability and functionality of T cell subpopulations. In contrast to its ability to initiate regulated cell death in cancer cells, treatment of PBMCs with increasing concentrations of BPM31510 lead to an increased frequency of viable CD3+ cells. Further phenotypic analysis revealed that cytotoxic T cells (CD8+/CD3+) and T helper cells (CD4+/CD3+), as well as NKT cells (CD56+/CD3+), contributed to the observed increase in T cell frequency. Proliferation measurements by EdU-incorporation indicated enhanced cytotoxic T cell proliferation in BPM31510 treated PBMCs, and likewise, BPM31510 increased degranulation of activated cytotoxic T cells, as indicated by measurement of plasma membrane-exposed lysosomal-associated membrane protein 1 (CD107a). Consistent with the ex vivo observations, in vivo studies using the syngeneic MC38 murine tumor model demonstrated that BPM31510 administration resulted in a dose-dependent enhancement of the number of CD3+ cells in the tumor microenvironment with cytotoxic T cells (CD8+/CD3+) representing the largest population. Together, these data define a supportive effect of BPM31510 on T cell frequency, viability, and functionality. In addition, in ex vivo activated PBMCs, BPM31510 decreased the percentage of PD1+ T cells while simultaneously increasing the percentage of PD1- T cells in the population. Moreover, in the PD1+ T cell population, PD1 expression on the cell surface was increased while PD1- T cells experienced no change in cell surface expression of PD1. These data suggest BPM31510 treatment promotes highly functional cytotoxic T cells while cells with early signs of exhaustion are induced to follow the path of exhaustion and elimination. Collectively, these results define an immune-modulatory activity for BPM31510, particularly in the T cell compartment, in part, through regulation of T cell exhaustion; this may have important implications for the use of BPM31510 in ‘immunologically cold' tumor types or in combination with immune checkpoint blockade strategies.
Citation Format: Maria Nastke, Shiva Kazerounian, Nidhi Gaur, Shyamali Jayashankar, David Linsenmayer, Carrie Spencer, Arun Nambiar, Aishwarya Sarma, Anne R. Diers, Stephane Gesta, Vivek Vishnudas, Vikas P. Sukhatme, Niven R. Narain, Rangaprasad Sarangarajan. Immuno-modulatory activity of BPM31510 supports T cell viability, proliferation, and function while reversing early signs of exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4724.