Abstract A011: IL-12 armored anti-macrophage CAR T cells reset and reprogram the tumor microenvironment to control metastatic ovarian and lung tumor growth

Abstract Background: CAR T cell therapy has shown limited success in solid tumors due to scarce tumor-specific antigens and an immunosuppressive tumor micro-environment (TME) driven by tumor-associated macrophages (TAMs). To address this, we engineered CAR T cells to eliminate TAMs and locally deliver immunostimulatory cytokines. Methods: We generated chimeric antigen receptor (CAR) targeting FOLR2 and TREM2, two surface molecules highly and specifically expressed on TAMs. We also engineered the vectors to express IL-12, a pro-inflammatory cytokine. We tested the IL-12 anti-FOLR2 CAR T and IL-12 anti-TREM2 CAR T in syngeneic, orthotopic models of metastatic ovarian and lung cancer, respectively. Results: In an aggressive ovarian tumor model in which control animals succumbed within 35 days of implantation, treatment with IL-12 anti-FOLR2 CAR T cells induced rapid tumor regression within 3 weeks and extended survival beyond 95 days. Importantly, this was achieved with only 105 CAR T cells, without preconditioning, and with negligible toxicity. Similarly, survival nearly doubled when we treated immunocompetent mice with aggressive lung tumors with 1.5 × 105 IL-12 anti-TREM2 CAR T cells (without preconditioning) compared to the control T cell-treated group. Examination of the tumor microenvironment revealed a sustained IFNγ/IL-12 response signature that persisted long after the disappearance of the IL-12-armored CAR T cells. This drove significant infiltration of tumor-antigen-specific activated endogenous T cells and a substantial expansion of Cxcl9+ immunostimulatory macrophages, which provided chemoattractant and activation signals to the T cells. The same IL-12–driven response also induced robust upregulation of FAS on tumor cells, and tumor control was significantly reduced upon FAS ablation in cancer cells, underscoring the contribution of the FAS pathway in mediating tumor clearance. Conclusions: These results demonstrate IL-12-armored CAR T targeting tumor-associated macrophages enables significant and lasting anti-tumoral effects in preclinical models of two aggressive cancers by resetting and reprogramming the TME, inducing FAS-mediated killing, and activating endogenous immunity with limited toxicity. Citation Format: Jaime Mateus-tique, Ashwitha Lakshmi1, Bhavya Singh, Alfonso Rodriguez, Rhea Iyer, Chiara Falcomata, Matthew Lin, Gvantsa Pantsulaia, Alexander Tepper, Trung Nguyen, Angelo Amabile, Gurkan Mollaoglu, Luisanna Pia, Divya Chhamalwan, Hunter Potak, Marco Colonna, Alessia Baccarini, Joshua Brody, Brian Brown, Miriam Merad. IL-12 armored anti-macrophage CAR T cells reset and reprogram the tumor microenvironment to control metastatic ovarian and lung tumor growth abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A011.