Abstract 4008: A novel, first in class chimeric antigen receptor dendritic cell platform driving broad and durable antitumor immunity in solid tumors

Abstract Chimeric Antigen Receptor Dendritic Cells (CAR-DCs) represent a new class of immunotherapy designed to overcome the key limitations of CAR-T and immune checkpoint blockade (ICB) in solid tumors. By engineering conventional dendritic cells (cDCs) with a tumor-targeting CAR delivered via non-integrating mRNA, we have harnessed the intrinsic ability of DCs to cross-prime a broad repertoire of antitumor CD8+ T cells. This approach merges the precision of CAR technology with the natural antigen-presenting potency of DCs, enabling broad immune activation by inducing polyclonal CD8+ T-cell responses that extend beyond CAR-restricted epitopes. To enable clinical advancement, we have developed a scalable human manufacturing process that reliably produces >300 million CAR-DCs, overcoming a longstanding barrier to the translational deployment of DC-based therapies. Immunotherapies such as CAR-T and ICB have transformed hematologic cancer treatment but remain ineffective in many solid tumors due to finite target antigens and dependance on pre-existing tumor-reactive T cells. To overcome these challenges, we engineered type I conventional DCs with a CAR recognizing B7-H3, a clinically relevant solid and liquid tumor antigen. In vitro, B7-H3 CAR-DCs displayed enhanced uptake of diverse tumor antigens, maturation, and superior cross-presentation of tumor derived antigens to CD8+ T cells, driving potent cytotoxic T-cell activation. In vivo, using a C57BL/6 syngeneic 1956 sarcoma model comprised of 75% B7-H3+ and 25% B7-H3- tumor cells, untreated mice exhibited progressive disease. In contrast, both intratumoral and intravenous administration of B7-H3 CAR-DCs induced complete to almost complete tumor regression and confer durable protection upon rechallenge, demonstrating the establishment of robust, target-independent immunity. Analysis of tumor-draining lymph nodes (tdLNs) revealed that B7-H3 CAR-DCs delivered substantially greater amounts of tumor antigen to tdLNs. Correspondingly, transcriptional profiling of tdLN CD8+ T cells revealed signatures of enhanced activation, increased proliferative potential, and a shift toward memory formation which are hallmarks of efficient cross-priming. Mass spectrometry of MHC-I-cross presented peptides and tetramer analyses demonstrated CAR-DCs generated a broad expansion of endogenous tumor neoantigen-specific CD8+ T cells, confirming strong and effective diversification of the antitumor T-cell response. Together, these results position mRNA-engineered CAR-DCs as a first-in-class, translationally ready cell therapy platform that integrates antigen specificity, broadening of the antitumor T-cell response, durable memory formation, and GMP-compatible large-scale manufacturing thereby supporting rapid advancement toward IND-enabling studies and clinical evaluation in solid tumors. Citation Format: Shelby L. Namen, Gaurav Pandey, Teri Naismith, Colin Willoughby, Lizzie Longtine, Usman Panni, Cheryl F. Lichti, Kartik Singhal, Malachi Griffith, Carl DeSelm. A novel, first in class chimeric antigen receptor dendritic cell platform driving broad and durable antitumor immunity in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4008.