Abstract 1680: BPM31510, an anti-cancer agent selectively causes activation and proliferation of T cells, demonstrating potential utility in an immune-oncology setting

Abstract

Abstract BPM 31510, a clinical stage, nanodispersion of ubidecarenone has a unique mechanism of action that effectuates an anti-Warburg switch in cancer cell metabolism and activation of apoptosis. Given the observed central role of BPM 31510 in regulating mitochondrial function in cancer cells, it is of great interest to investigate the ability of BPM 31510 to modulate immune cells and their functionality. Therefore, the effects of BPM 31510 on peripheral blood mononuclear cells (PBMCs) were investigated to elucidate the immuno-metabolic mechanism of BPM 31510. Healthy donor PBMCs activated with PHA or PWM was used as model system, and the effect of BPM 31510 on immune cells viability was determined using flow cytometry. In addition, the effect of BPM31510 on immune cell function was evaluated by measuring a panel cytokines released in these cells, using a quantitative ELISA platform from Meso Scale Discovery. Results: BPM 31510 has been shown in previous studies to effectively induce apoptosis on a variety of cancer cell lines while sparing normal cells. Interestingly, 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 cells frequency. On the other hand, B cells (CD19+), NK cells (CD56+/CD3-), and the monocytes (CD14+) showed a decrease in frequency, an effect reflected also by a reduction in viability with increasing BPM 31510 concentrations. Cytokine analysis indicated that effector cytokines IL-2, IFN-γ, and TNF- α were secreted at significantly higher levels with increasing concentration of BPM 31510. Interestingly, IL-10 level, an immuno-regulatory cytokine, was strongly decreased in the supernatant of PBMCs treated with BPM31510. Taken together, we demonstrated that BPM 31510 has a direct effect on immune cells and their functionality. Although BPM 31510 induced apoptosis of cancer cells, our data indicate that it supports cell proliferation of T cells, and effector function of adaptive immune cells, likely by providing a higher energy supply for effector T cells. Subsequently, a higher activation state of effector T cells may result in increased levels of cytotoxic effector molecules (perforin, granzymes, Fas ligand) and macrophage activating effector molecules (IFN-γ, IL-2, TNF-α) which supports and attracts other immune cells like NK cells to the tumor. Citation Format: Maria-D Nastke, Nidhi Gaur, Louisa Dowal, Samantha Fowler, Anne Diers, Stephane Gesta, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan. BPM31510, an anti-cancer agent selectively causes activation and proliferation of T cells, demonstrating potential utility in an immune-oncology setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1680. doi:10.1158/1538-7445.AM2017-1680