Abstract 6106: A regulated, cell-intrinsic cytokine engineering strategy to enhance the in vitro and in vivo persistence of iPSC-derived CAR-T cell therapies

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Abstract Large-scale clinical production of induced pluripotent stem cell (iPSC)-derived CAR-T cells represents a remarkable opportunity in allogeneic cell therapies. Despite the growing advantages offered by iPSCs such as multiplex gene editing and unlimited starting material, most iPSC derived CAR-T cells demonstrate limited clinical proliferation and persistence. This has been partially attributed to existing iPSC differentiation protocols that yield only cytotoxic CD8 T-cells, whereas conventional autologous and donor-derived CAR-T therapies contain a mixture of CD8 and supportive CD4 T-cells. It has been established that cytokine signaling via the JAK/STAT pathway plays an important role in promoting CAR-T cell function. Herein we describe novel engineered receptors that can induce JAK/STAT signaling in iPSC derived CD8 T-cells. We show that iPSC derived CD8 T-cells have a unique JAK/STAT signaling requirement for long-term cytotoxicity and proliferation in our in vitro assays. We show that our engineered receptors can induce JAK/STAT signaling in the absence of exogenous cytokines in culture media. When fully differentiated CD8 T-cells are transduced with engineered cytokine receptors, they show long-term persistence in the absence of exogenous cytokines in vitro. We observed that premature activation of JAK/STAT signaling pathways can skew cells toward a myeloid or innate lymphoid cell lineage. To circumvent this, we designed iPSC clones with an engineered cytokine receptor integrated into a specific locus under the control of context-specific regulatory sequences. These designs exhibited a stringent off-state during differentiation and CAR-dependent transcriptional responsiveness when exposed to target antigen. This data reveals that a regulated strategy can control cytokine receptor expression during differentiation, to preserve phenotype and improve efficacy of differentiated cells. Further, constitutive activation of JAK/STAT signaling may drive adverse side-effects, and we demonstrate that our regulated designs show complete lack of activity in the absence of antigen stimulation. Finally, we evaluated iPSC derived CD8 T-cells harboring the regulated cytokine engineering strategy in vivo. Engineered iPSC derived CD8 T-cells showed tumor growth inhibition and persistence in the absence of exogenous cytokines in a disease relevant lymphoma Raji model. Engineering of appropriate cytokine support and strategies to regulate expression during differentiation is an important first step to enhance the persistence of iPSC derived CD8 T-cells. A major advantage of using iPSC derived CD8 T-cells is their potential for drug re-administration without toxic lymphodepletion and exogenous cytokine support. We believe that cell-intrinsic cytokine support is critical to develop durable and safe allogeneic T-cell therapies for patients. Citation Format: Siddarth Chandrasekaran, Justin Yoo, Michael H. Cadell, Laura Prochazka, Elisa Martinez, Jen F. Lai, Muluken S. Belew, Amanda AuYeung, Chris Saxby, Omar Subedar, Zahra Sahaf, Dylan Lee, Sommer Apelu, Libin Abraham, Chloe Hurling, Vaisakh Rajan, Shruti Sharma, Charlie Liu, Richard Carpenedo, Shri Joshi, Elizabeth Csaszar, Emily Titus, Chris Bond. A regulated, cell-intrinsic cytokine engineering strategy to enhance the in vitro and in vivo persistence of iPSC-derived CAR-T cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6106.

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