In Vivo Engineering of Virus-Specific T Cells for CAR T Cell Therapy Against Multiple Myeloma

The clinical benefit of CAR T cells that target B Cell Maturation Antigen (BCMA) for multiple myeloma (MM) patients has led to landmark regulatory approvals since 2021. Yet clinical application of CAR T cells in MM has been hampered by prohibitive costs and manufacturing issues including lengthy vein-to-vein time, severely limiting patient access. While ‘off-the-shelf’ BCMA-directed CD3 T cell engagers have also received accelerated approvals, their short half-lives require frequent and ongoing dosing. Emerging strategies to solve these challenges include in vivo engineering of circulating T cells, using viral vectors or polymeric/lipid nanoparticles functionalized with pan-T cell antibodies to deliver plasmid DNA or mRNA encoding CAR transgenes. While promising, the limited specificity of these approaches can lead to transfection of autoimmune and regulatory T cells, which can increase off-target toxicity, break self-tolerance and reduce treatment efficacy. This proposal seeks to develop Ag-presenting lipid nanoparticles (APNs) to deliver BCMA CAR mRNA to defined immune effector cell subsets for MM treatment. Therapy studies will be evaluated using MM mouse models grafted with both non-autologous (i.e., healthy donors) and autologous (i.e., patient derived) T cells. In both models, the impact of boosting BCMA CAR T cells using dendritic cell vaccines will be evaluated. The use of animal models is necessary for this project to emulate critical features such as systemic immune interactions, full tumor microenvironment heterogeneity, trafficking and persistence of CAR T cells, and whole-body pharmacokinetics and toxicity profiles. These can only be assessed in an in intact physiological system and murine models represent the least sentient system capable of accounting for these immune and biological responses. If successful, the proposal is expected to impact myeloma patients by significantly reducing manufacturing complexities, lowering costs, improving anti-cancer responses and broadening patient access to BCMA CAR T cell therapy. Project Number: 1R01CA304559-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Gabriel Kwong (+1 co-PI) | Institution: GEORGIA INSTITUTE OF TECHNOLOGY, ATLANTA, GA | Award Amount: $705,899 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BBBT-X (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11367782