Abstract 144: In vivo CAR mRNA engineering of both adaptive and myeloid cells enables potent anti-tumor control of solid cancers.

Abstract Background: In solid tumors, chimeric antigen receptor (CAR) T cell therapies are limited by their inability to overcome poor trafficking, antigen heterogeneity and the immunosuppressive myeloid cells in the tumor microenvironment (TME). Here, we introduce in vivo multi-immune cell programming designed to precisely and simultaneously program multiple immune cell types using a single engineered product. This approach builds on the clinical experience with in vivo CAR-mRNA engineered CAR myeloid cells that created a pro-inflammatory tumor environment. Combining non-targeted and targeted LNP delivery, optimized mRNA, and cell-specific CAR architecture, we endow myeloid cells, NK cells and T cells with tailored effector functions. Methods: Anti-HER2 CAR mRNAs optimised for myeloid, NK or T cell signalling were encapsulated in LNPs and delivered intravenously. Anti-tumor efficacy was evaluated in immunocompetent hHER2 transgenic mice bearing syngeneic hHER2-MC38 colon adenocarcinoma tumors. Results: In a colorectal tumor model, myeloid- and NK-cell reprogramming with CAR mRNA/LNPs drove tumor regression, prolonged survival, remodeling of the tumor microenvironment, greater antigen presentation, and enhanced T-cell infiltration and activation. Likewise, T cell engineered with CAR mRNA/tLNPs elicited robust anti-tumor activity. Notably, co-delivery of cell-specific CAR mRNA/LNPs to both myeloid and T-cell compartments produced even stronger tumor control, highlighting the power of coordinated multi-lineage immune engineering. Conclusions: This work demonstrates that simultaneous In vivo engineering of myeloid cells, T cells, and NK cells with CARs can orchestrate the coordinated actions of both innate and adaptive immunity for potent anti-tumor activity. This strategy offers a scalable and off-the-shelf approach for cell therapy and establishes a new therapeutic paradigm for overcoming the complexity of solid tumors. Citation Format: Junming Tong, Moore Chen, Kevin Sek, Meghan Harris, Jerome Chal, Colin Pouton, Angus Johnston, Daniel Getts, Robert Hofmeister, Phil Darcy, Jian Ding. In vivo CAR mRNA engineering of both adaptive and myeloid cells enables potent anti-tumor control of solid cancers [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 144.