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Review
. 2014 Jan;257(1):107-26.
doi: 10.1111/imr.12131.

Design and Development of Therapies Using Chimeric Antigen Receptor-Expressing T Cells

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Free PMC article
Review

Design and Development of Therapies Using Chimeric Antigen Receptor-Expressing T Cells

Gianpietro Dotti et al. Immunol Rev. .
Free PMC article

Abstract

Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking, and effector functions of a T cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CAR-T cells. Our review then describes our own and other investigators' work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained.

Keywords: CAR; T cells; cancer; gene therapy; immunotherapy.

Figures

Fig. 1
Fig. 1. CAR Design
(A) CARs consist of an ectodomain, commonly derived from a single chain variable fragment (scFv), a transmembrane domain, and an endodomain. (B) Depending on the number of signaling domains, CARs are classified into 1st generation (one), 2nd generation (two), or 3rd generation (three) CARs.
Fig. 2
Fig. 2. Critical CAR components
Optimal CAR activity is determined by epitope location, scFv affinity, hinge and transmembrane domains, and number of signaling domains.
Fig. 3
Fig. 3. T-cell subsets
The phenotypic properties of T-cell subsets. − indicates absence and + presence of the specific cell surface marker. Functional properties for each subset are also shown. − indicates lack of the functional property; +, ++, +++ indicates the degree (low, intermediate, high) of the specific property.
Fig. 4
Fig. 4. Immune evasion strategies of tumors
Malignant cells and their supporting stroma 1) secrete immunosuppressive cytokines such as transforming growth factor-β (TGFβ) or interleukin-10 (IL-10); 2) attract immunosuppressive cells such Tregs or MSDCs; 3) inhibit dendritic cell maturation; 4) express molecules on the cell surface that suppress immune cells including FAS-L and PD-L1, and; 5) create a metabolic environment (e.g. high lactate, low tryptophan) that is immunosuppressive.
Fig. 5
Fig. 5. Overcoming tumor-mediated immunosuppression
Countermeasures can be divided into the following strategies: 1) increasing the level of CAR-T-cell activation or decreasing physiological downregulation; 2) engineering the CAR-T cells to be resistant to the immune evasion strategies used by the tumor; and 3) targeting the cellular components of tumor stroma.

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