title: T cell activation upon exposure to patient-derived tumor tissue: a functional assay to select patients for adoptive T cell therapy.
abstract: 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 IFNgamma, TNFalpha, 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.
authors.affiliation: Dept Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schroten
authors.forename: Robert
authors.initials: R
authors.lastname: Kraaij
authors.forename: Joke L M
authors.initials: JL
authors.lastname: Veldhoven
authors.forename: Cor A
authors.initials: CA
authors.lastname: Berrevoets
authors.forename: Michael A
authors.initials: MA
authors.lastname: den Bakker
authors.forename: Qiangzhong
authors.initials: Q
authors.lastname: Ma
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Chris H
authors.initials: CH
authors.lastname: Bangma
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Willemsen
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000937:Antigen-Antibody Reactions; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D005818:Genetic Engineering; D006801:Humans; D019169:Jurkat Cells; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000276:immunology*; D018579:Patient Selection; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases