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T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells

  • Author(s): Zah, E
  • Lin, MY
  • Silva-Benedict, A
  • Jensen, MC
  • Chen, YY
  • et al.
Abstract

© 2016 American Association for Cancer Research. The adoptive transfer of T cells expressing anti-CD19 chimeric antigen receptors (CARs) has shown remarkable curative potential against advanced B-cell malignancies, but multiple trials have also reported patient relapses due to the emergence of CD19-negative leukemic cells. Here, we report the design and optimization of single-chain, bispecific CARsthat trigger robust cytotoxicity against target cells expressing either CD19 or CD20, two clinically validated targets for B-cell malignancies. We determined the structural parameters required for efficient dual-antigen recognition, and we demonstrate thatoptimized bispecificCARs can control both wildtype B-cell lymphoma and CD19- mutants with equal efficiency in vivo. To our knowledge, this is the first bispecific CAR capable of preventing antigen escape by performing true OR-gate signal computation on a clinically relevant pair of tumor-associated antigens. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptorswith higher-level complexity.

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