Abstract A122: Improving antitumor T cell therapy with membrane-tethered engineered cytokine agonists (MECAs)

Abstract Background: Chimeric antigen receptor (CAR) T cell therapy has demonstrated marked success in the control of hematological malignancies. However, CAR T cell therapy has been less successful when applied to solid tumors. This has been attributed to multiple factors including tumor infiltration, antigen heterogeneity, and the immunosuppressive tumor microenvironment. The hostile milieu and chronic exposure to antigen that CAR T cells face in the tumor microenvironment induces T cell exhaustion which is associated with an overall loss of therapeutic efficacy. Methods: Strategies for overcoming T cell exhaustion are central to improving CAR T cell efficacy in the treatment of solid tumors. The incorporation of survival-promoting proteins, such as cytokines, into CAR T cells have been used to generate a supportive local immune environment. Interleukin-2 (IL-2) is a cytokine that acts as a potent growth factor in T cells; however, therapeutic application of systemic IL-2 has been associated with severe toxicities and T cell exhaustion. To address this, we have developed membrane-tethered engineered cytokine agonists (MECAs) that anchor IL-2 and IL-2 partial agonists to the cell surface membrane of CAR T cells, restricting their signaling to the expressing cells to maximize autocrine signaling and prevent toxicity. Results: Here, we evaluate the influence of MECAs on the proliferation, exhaustion state, and cytotoxic function of CAR T cells. CAR T cells expressing the MECAs demonstrated improved cytotoxic function and proliferation with in vitro models. MECA expressing CAR T cells did not cause toxicity in control mice or in an orthotopic glioma model. Preliminary results from the toxicity study indicate improved in vivo antitumor activity of MECA expressing CAR T cell compared to CAR only. Conclusion: Exhaustion of antigen-specific T cells is a challenge in multiple cancer immunotherapy modalities, and the proposed MECAs have the potential to revolutionize immunotherapy for solid tumors as an effective and widely applicable solution. Citation Format: Diana Gumber, Saul Priceman, Christine J Brown, Leo Wang. Improving antitumor T cell therapy with membrane-tethered engineered cytokine agonists (MECAs) [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A122.