T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells

TLDR

Adoptive transfer of anti‑CD19 CAR T cells shows curative potential against B‑cell malignancies, yet relapses occur from CD19‑negative leukemic cells. The study aims to design and optimize bispecific CARs targeting CD19 or CD20 to enhance cytotoxicity against B‑cell malignancies. The bispecific CAR was engineered by optimizing structural parameters for dual‑antigen recognition and is compatible with standard manufacturing, enabling in vivo control of both wild‑type and CD19‑negative B‑cell lymphoma. The bispecific CAR prevents antigen escape by OR‑gate signaling between CD19 and CD20, offering an effective solution to CD19 CAR T‑cell relapse and demonstrating the power of structure‑based design. Published in Cancer Immunology Research, 4(6):498–508, ©2016 AACR, with a related Spotlight and addendum.

Abstract

Abstract 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 CARs that 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 that optimized bispecific CARs can control both wild-type 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 receptors with higher-level complexity. Cancer Immunol Res; 4(6); 498–508. ©2016 AACR. See related Spotlight by Sadelain, p. 473. An addendum has been published.