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 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.
Schroten
Caroline
C
Dept Urology, Erasmus MC, Rotterdam, The Netherlands.
Kraaij
Robert
R
Veldhoven
Joke L M
JL
Berrevoets
Cor A
CA
den Bakker
Michael A
MA
Ma
Qiangzhong
Q
Sadelain
Michel
M
Bangma
Chris H
CH
Willemsen
Ralph A
RA
Debets
Reno
R
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
D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases