Abstract C005: Understanding the Role of Tonic TCR Signaling to Optimize CAR-T Efficacy

Abstract CAR T cell therapy achieves impressive remission rates in hematologic malignancies, yet clinical durability remains a persistent challenge. Autologous CAR T cell products require time-intensive individualized manufacture, while allogeneic CAR T cells demonstrate shortened persistence compared to autologous counterparts. Recent mechanistic insights reveal that endogenous TCR signaling through weak self-pMHC interactions provides essential homeostatic cues that support long-term CAR T cell survival and memory formation. However, current manufacturing paradigms treat native TCR signaling as a binary choice: either fully preserved or entirely deleted. We hypothesize that tonic TCR signaling functions as a tunable parameter rather than an on/off switch, and that CD5, an ITIM-bearing inhibitory receptor that marks tonic signal strength, represents a rational therapeutic target for optimizing CAR T cell fitness. Critically, the field lacks clarity on whether CD5 is mechanistically required for CAR T cell durability or merely marks cells with inherently superior developmental history. This distinction is fundamental: if CD5 is mechanistically required, next-generation CAR T therapies can be rationally engineered to fine-tune CD5 expression or target CD5-dependent signaling pathways. If CD5 is predictive only, alternative upstream mechanisms must be identified and targeted. Our work directly addresses this gap by empirically testing whether CD5 manipulation alters CAR T cell fitness and by identifying the specific signaling and transcriptional nodes that CD5 controls. By establishing the mechanistic role of CD5 in tonic signaling, we will deliver quantitative rules for calibrating native TCR input in both autologous and allogeneic CAR T products, enabling the design of safer, more durable, and more accessible CAR T therapies across patient populations. Citation Format: Samuel D. Burciaga, Michael Yarnell, Lily Mussallem, Amanda Novak, Ross Kedl, Terry Fry. Understanding the Role of Tonic TCR Signaling to Optimize CAR-T Efficacy [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 C005.