To improve CAR T cell antigen targeting and reduce associated toxicities, Salzer et al. studied how CAR dimerization can regulate antigen recognition and sensitivity. For CARs with low-, but not high-affinity single binding domains, receptor dimerization was required for target cell lysis and IFNγ secretion, and could be engineered to respond to a small-molecule or soluble-antigen dimerizer. These avidity-controlled CARs (AvidCARs) enabled effective AND-gate logic and depended on receptor dimerization. In vivo, avidCAR T cells under the control of a small-molecule dimerizer specifically lysed target cells and extended survival of leukemia-bearing mice.
Contributed by Alex Najibi
ABSTRACT: T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.
Author Info: (1) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. Christian Doppler Laboratory for Next Generation CAR T Cells, 1090, Vienna, Austria. (2) St. Anna C
Author Info: (1) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. Christian Doppler Laboratory for Next Generation CAR T Cells, 1090, Vienna, Austria. (2) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. (3) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. Christian Doppler Laboratory for Next Generation CAR T Cells, 1090, Vienna, Austria. (4) Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, 1090, Vienna, Austria. (5) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. (6) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. (7) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. (8) Department of Biotechnology, University of Natural Resources and Life Sciences, 1190, Vienna, Austria. (9) Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. (10) Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, 1090, Vienna, Austria. (11) Department of Chemistry, Institute of Biochemistry, University of Natural Resources and Life Sciences, 1190, Vienna, Austria. (12) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. (13) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. Department of Pediatrics, St. Anna Kinderspital, Medical University of Vienna, 1090, Vienna, Austria. (14) Christian Doppler Laboratory for Next Generation CAR T Cells, 1090, Vienna, Austria. michael.traxlmayr@boku.ac.at. Department of Chemistry, Institute of Biochemistry, University of Natural Resources and Life Sciences, 1190, Vienna, Austria. michael.traxlmayr@boku.ac.at. (15) St. Anna Children's Cancer Research Institute (CCRI), 1090, Vienna, Austria. manfred.lehner@ccri.at. Christian Doppler Laboratory for Next Generation CAR T Cells, 1090, Vienna, Austria. manfred.lehner@ccri.at. Department of Pediatrics, St. Anna Kinderspital, Medical University of Vienna, 1090, Vienna, Austria. manfred.lehner@ccri.at.
