Abstract 4097: Functional and translatable efficacy of CAR-T cells targeting B cell lymphomas

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Abstract Chimeric Antigen Receptor (CAR)-T cell therapy has achieved great success in treating a variety of liquid tumors, in particular CD19+ lymphomas. CAR technology is advancing rapidly, with notable improvements in efficacy, safety and complexity as human ingenuity seeks solid tumor applicability. Here we describe how to efficiently generate, expand and validate in-vitro and in-vivo efficacy of a clinically tested CD19-specific CAR. HLA-A*02:01+ CD3+ T-cells were transduced to express a CD19-CAR to >80% efficiency (in 5 donors) and reproducibly expanded to >68 fold over a 19 day period. In-vitro studies were used to assess tumor killing ability, utilizing a HLA-A*02:01+ patient derived xenograft (PDX) CD19+ cell line, alongside human cancer cell lines RAJI (CD19+) and K562 (CD19-). Analysis revealed the potent ability of CD19-CAR-T cells to specifically target CD19+ cells in a dose dependent manner. Supernatant analysis showed highly elevated IFNγ concentrations, identifying enhanced activation of CAR-T cells in the presence of CD19+ target cells only. In-vivo survival studies were completed to identify translatability & efficacy in both systems. Mice were inoculated with CD19+ cells to produce multiple tumor burdened models (RAJI, JEKO-1 & PDX4009). This demonstrated high efficacy of CAR-T at targeting both tumor cell line RAJI or PDX in vivo, with almost complete tumor regression seen in both models. JEKO-1 tumors saw progression slowed in comparison to non-transduced or no treatment controls however due to the nature of this cell line (highly tumorigenic) the level of tumor regression was not matched to the other models. Cell bio-distribution was assessed with CAR-T cells tracking successfully to the tumors as well as the highly vascularized tissues, which was expected and consistent with previous data. These assays can be translated to any CAR construct aimed at targeting either solid or hematological tumors and demonstrates an integrated platform for translating CAR research that can be utilized end to end. Citation Format: Lauren Kelsey, Karin Latta, Joey Kolb, Bincy John, Ilona Aylott, Daniel Rocca, Alexandru Bacita, Christopher Kirkham, Patrick Walters, Charlotte Humphery, Lorena Sueiro Ballesteros, Jezrom Self-Fordham, Louise Brackenbury, Chassidy Hall, Harris David, Julia Schueler, Robert Nunan. Functional and translatable efficacy of CAR-T cells targeting B cell lymphomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4097.

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