A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor.
Adoptive immunotherapies composed of T cells engineered to express a chimeric antigen receptor (CAR) offer an attractive strategy for treatment of human cancer. However, CARs have a fixed antigen specificity such that only one tumor-associated antigen (TAA) can be targeted, limiting the efficacy that can be achieved because of heterogeneous TAA expression. For this reason, a more generalized and effective application of CAR therapy would benefit from the capability to produce large panels of CARs against many known TAAs. In this study, we show a novel strategy to extend the recognition specificity potential of a bioengineered lymphocyte population, allowing flexible approaches to redirect T cells against various TAAs. Our strategy employs a biotin-binding immune receptor (BBIR) composed of an extracellular-modified avidin linked to an intracellular T-cell signaling domain. BBIR T cells recognized and bound exclusively to cancer cells pretargeted with specific biotinylated molecules. The versatility afforded by BBIRs permitted sequential or simultaneous targeting of a combination of distinct antigens. Together, our findings show that a platform of universal T-cell specificity can significantly extend conventional CAR approaches, permitting the tailored generation of T cells of unlimited antigen specificity for improving the effectiveness of adoptive T-cell immunotherapies for cancer.
Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Katarzyna
K
Urbanska
Evripidis
E
Lanitis
Mathilde
M
Poussin
Rachel C
RC
Lynn
Brian P
BP
Gavin
Sander
S
Kelderman
Jason
J
Yu
Nathalie
N
Scholler
Daniel J
DJ
Powell
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000502:physiology; D019921:Biotinylation; D015815:Cell Adhesion Molecules / Q000502:physiology; D002460:Cell Line; D000071858:Epithelial Cell Adhesion Molecule; D000939:Epitopes; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D000939:Epitopes; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma