Abstract 3975: A therapeutic screening platform for assessing antigen-specific T cell-mediated tumor killing in vitro

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Abstract Many cancers remain resistant to conventional therapies, consequently there has been an exponential rise in the number of therapeutics harnessing the power of the immune system in an oncology setting, with several remarkable examples of success. High frequencies of infiltrating tumor-specific T cells have been linked to improved patient outcomes, which highlights the importance of uncovering how therapeutics can enhance their function. To explore this functionality in a preclinical setting it is critical to have physiologically relevant models. Here, we demonstrate that common issues, such as low precursor frequencies and restricted HLA-types can be overcome via access to HLA-typed samples and use of expansion platforms which attain high numbers of antigen-specific T cells. Furthermore, we show how these systems enable vaccine immunogenicity screening and assessment of therapeutic efficacy. Healthy blood donations were screened for HLA type and antigen-specific T cells were expanded by either co-culture with peptide-pulsed dendritic cells or polyclonal stimulation following multimer enrichment and FACS sorting. Following expansion, the large number of antigen-specific T cells generated enabled the T cells to be assessed via phenotyping, cytokine secretion, or functional killing assays in a 2D or 3D tumor setting. Tumor targets with either 1) endogenous antigen expression, 2) antigen introduced via lentiviral overexpression or 3) peptide loading of MHC class I were utilized. Validated readouts for measuring antigen-specific killing included flow cytometry and time-lapse imaging (IncuCyte), alongside quantification of antigen-specific IFNɣ responses by ELISpot. These pre-clinical platforms represent a suite of physiologically relevant T cell assays which can be used to perform candidate selection in tumor associated antigen/neoantigen vaccine drug development programs, pharmacological inhibition of checkpoint pathways, or co-stimulatory agonist discovery. In combinatorial approaches with radio- or chemotherapy, the development of novel immunotherapies offers hope to many patients with treatment-resistant cancers. Citation Format: Elsenoor Klaver, Henry Leonard, Elizabeth Lieverse, Oliver Brand, Olivier Reelfs, Christopher Kirkham, Lauren Schewitz-Bowers, Louise Brackenbury. A therapeutic screening platform for assessing antigen-specific T cell-mediated tumor killing in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3975.

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