T cell activation upon exposure to patient-derived tumor tissue: A functional assay to select patients for adoptive T cell therapy
Gene-engineered T cell therapy represents a promising strategy to treat cancers. To enable pre-selection of patients sensitive to this type of treatment we have setup and validated a T cell activation assay to test antigen expression on patient-derived tumor tissues. Chimeric antibody-based receptor (CAR) directed against CAIX, currently used in a clinical trial to treat RCC patients, was used as a model receptor. Primary human T cells expressing CAIX CAR were able to respond to CAIX-positive but not CAIX-negative tumor tissue and showed an increased production of IFNγ, TNFα, IL-10 and IL-4, but not IL-2 or IL-5. Tumor tissue driven responses of primary T cells were paralleled by NFAT activation measured in CAR-transduced Jurkat T cells, which was shown to be triggered in a CAR and antigen-specific manner. Next, the reporter gene assay was applied to two independent PSMA CARs, which both mediated NFAT activation in response to tumor tissue. Taken together, a sensitive and donor-independent assay was established to measure T cell activation upon exposure to patient-derived tumor tissue, which may facilitate pre-selection of patients for clinical adoptive T cell therapy.
|Keywords||Chimeric antibody-based receptor (CAR), Gene-modified T cells, NFAT reporter gene assay, Prostate cancer, T cell therapy, T lymphocyte, T lymphocyte activation, adoptive T lymphocyte therapy, adoptive transfer, antigen, antigen expression, antigen specificity, article, cancer tissue, carbonate dehydratase IX, cell assay, cell therapy, chimeric antibody, chimeric antibody based receptor, clinical trial, controlled study, cytokine production, gamma interferon, gene therapy, histopathology, human, human cell, human tissue, immunohistochemistry, interleukin 10, interleukin 2, interleukin 4, interleukin 5, kidney carcinoma, leukemia cell line, patient selection, priority journal, prostate specific membrane antigen, reporter gene, signal transduction, transcription factor NFAT, tumor necrosis factor alpha, unclassified drug|
|Persistent URL||dx.doi.org/10.1016/j.jim.2010.04.006, hdl.handle.net/1765/20683|
Schroten-Loef, C, Kraaij, R, Veldhoven, J.L.M, Berrevoets, C.A, den Bakker, M.A, Sadelain, M, … Debets, J.E.M.A. (2010). T cell activation upon exposure to patient-derived tumor tissue: A functional assay to select patients for adoptive T cell therapy. Journal of Immunological Methods, 359(1-2), 11–20. doi:10.1016/j.jim.2010.04.006