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Annu Rev Pharmacol Toxicol. 2016;56:59-83. doi: 10.1146/annurev-pharmtox-010814-124844.

Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy.

Gross G1,2,3, Eshhar Z3,4.

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Laboratory of Immunology, MIGAL, Galilee Research Institute, Kiryat Shmona 11016, Israel; email:
Department of Biotechnology, Tel-Hai College, Upper Galilee 12210, Israel.
Center of Cancer Research, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel; email:


A chimeric antigen receptor (CAR) is a recombinant fusion protein combining an antibody-derived targeting fragment with signaling domains capable of activating T cells. Recent early-phase clinical trials have demonstrated the remarkable ability of CAR-modified T cells to eliminate B cell malignancies. This review describes the choice of target antigens and CAR manipulations to maximize antitumor specificity. Benefits and current limitations of CAR-modified T cells are discussed, with a special focus on the distribution of tumor antigens on normal tissues and the risk of on-target, off-tumor toxicities in the clinical setting. We present current methodologies for pre-evaluating these risks and review the strategies for counteracting potential off-tumor effects. Successful implementation of these approaches will improve the safety and efficacy of CAR T cell therapy and extend the range of cancer patients who may be treated.


CARs; adoptive T cell therapy; cancer immunotherapy; chimeric antigen receptors; on/off-target effects; tumor antigens

[Indexed for MEDLINE]

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