CAR therapy: the CD19 paradigm
Michel Sadelain
Michel Sadelain
Published September 1, 2015
Citation Information: J Clin Invest. 2015;125(9):3392-3400. https://doi.org/10.1172/JCI80010.
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Review Series

CAR therapy: the CD19 paradigm

Abstract

Twenty-five years after its inception, the genetic engineering of T cells is now a therapeutic modality pursued at an increasing number of medical centers. This immunotherapeutic strategy is predicated on gene transfer technology to instruct T lymphocytes to recognize and reject tumor cells. Chimeric antigen receptors (CARs) are synthetic receptors that mediate antigen recognition, T cell activation, and — in the case of second-generation CARs — costimulation to augment T cell functionality and persistence. We demonstrated over a decade ago that human T cells engineered with a CD19-specific CAR eradicated B cell malignancies in mice. Several phase I clinical trials eventually yielded dramatic results in patients with leukemia or lymphoma, especially acute lymphoblastic leukemia (ALL). This review recounts the milestones of CD19 CAR therapy and summarizes lessons learned from the CD19 paradigm.

Authors

Michel Sadelain

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Figure 1

The first CARs and CCRs.

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The first CARs and CCRs. Top left: The first CD3ζ-chain fusions establis...
Top left: The first CD3ζ-chain fusions established the T cell–activating function of the CD3ζ-chain (26–28). The incorporation of an scFv diversified their antigen-binding capacity (23). Collectively, these receptors are now known as first-generation CARs. Bottom left: Derivation of the first CCR from the native CD28 costimulatory receptor (41). CCRs are not CARs, as they do not initiate T cell activation. The conflation of a first-generation CAR (top left) and a CCR (bottom left) resulted in the generation of a second-generation CAR capable of directing proliferation and sustained function of human peripheral blood T lymphocytes upon repeated exposure to antigen (right) (42).