Abstract 4217: MEKi in combination with anti-OX40 generates metabolically fit effector CD8+ T cells, enhances stem cell-like memory CD8+ T cells, and leads to strong anti-tumor activity

Abstract

Abstract In the tumor microenvironment (TME), T cell exhaustion and short persistence of effector cells are crucial factors that limit the efficacy of endogenously generated or adoptively transferred effector cells. Regenerative stem-cell memory CD62LhiCD44lowSca1+ CD8+ CD8+ T cells (TSCM) persist longer and produce cells with more vital effector functions. OX40, a member of TNFRSF4, has been shown to promote the expansion and proliferation of activated effector T cells, leading to the generation of robust anti-tumor responses and immune memory. However, treatment with anti-OX40 as a single therapeutic modality has not generated desirable clinical outcomes. A combination of immune modulators has been found to enhance the therapeutic efficacy synergistically. Recently, we reported that inhibition of MEK1/2 using selumetinib (AZD6244) leads to a significant increase in the numbers of CD8+ TSCM cells with self-renewability, enhanced multipotency and proliferative capacity, leading to potent anti-tumor effects. Therefore, here we combined selumetinib with anti-OX40 to investigate if enhanced immune-mediated anti-tumor responses could be obtained. Using three mouse tumor models (TC1, B16, and CT26), we found that combination of MEKi with anti-OX40 enhances the anti-tumor activity by increasing the expansion of total and antigen-specific CD8+ T cells in the TME. These CD8+ T cells have higher functional activity as seen by increased Granzyme B and INF-γ production. We also found similar results after adoptive cell therapy (ACT) where infusion of MEKi-treated cells in B16 tumor-bearing mice synergized with anti-OX40 agonist treatment. Interestingly, anti-OX40 treatment of MEKi-treated CD8+ T cells enhanced the metabolic fitness as demonstrated by low mitochondrial potential and enhanced Oxygen Consumption Rates (OCR), Spare Respiratory Capacity (SRC), and Extra-cellular Acidification Rates (ECAR) compared to anti-OX40 treatment alone. Furthermore, OX40 agonist significantly enhanced the longevity of MEKi-induced CD8+ TSCM cells. In summary, our data provide a novel strategy to utilize MEKi to enhance the efficacy of ACT and combination immunotherapy using anti-OX40 agonist. Citation Format: Pankaj Gaur, Vivek Verma, Mays Alreem Elayyan, Zainab Ramlaoui, Simon T. Barry, Viia E. Valge-Archer, Paul D. Smith, Seema Gupta, Samir N. Khleif. MEKi in combination with anti-OX40 generates metabolically fit effector CD8+ T cells, enhances stem cell-like memory CD8+ T cells, and leads to strong anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4217.