Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Oct:178:83-91.
doi: 10.1016/j.pharmthera.2017.03.012. Epub 2017 Mar 22.

Development of CAR T cells designed to improve antitumor efficacy and safety

Janneke E Jaspers  1 , Renier J Brentjens  2
Affiliations
Review

Development of CAR T cells designed to improve antitumor efficacy and safety

Janneke E Jaspers et al. Pharmacol Ther. 2017 Oct.

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are 'on-target, off-tumor' toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models.

Keywords: Armored CAR T cells; Chimeric antigen receptor; Costimulation; Cytokines; Genetic engineering; Tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement

R.J.B. is a co-founder, stockholder and consultant for Juno Therapeutics Inc. The authors declare no other conflicts of interest.

Figures

Fig. 1
Fig. 1
Summary of genetic strategies to improve CAR T cell function and antitumor activity. CAR: chimeric antigen receptor, iCAR: inhibitory CAR, CCR: chimeric costimulatory receptor, DN: dominant negative, PD-1: programmed cell death protein 1, αPD-L1 mAb: anti-PD-1 ligand 1 monoclonal antibody, shRNA: small hairpin RNA, solHVEM: soluble HVEM ectodomain protein, TME: tumor microenvironment.
See this image and copyright information in PMC

References

    1. Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E, Plotkin J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Science Translational Medicine. 2014;6(261):261ra151. - PMC - PubMed
    1. Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, et al. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992;357(6373):80–82. - PubMed
    1. Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunology Research. 2014;2(2):112–120. - PMC - PubMed
    1. Beatty GL, O’Hara M. Chimeric antigen receptor-modified T cells for the treatment of solid tumors: Defining the challenges and next steps. Pharmacology & Therapeutics. 2016;166:30–39. - PMC - PubMed
    1. Berger C, Flowers ME, Warren EH, Riddell SR. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood. 2006;107(6):2294–2302. - PMC - PubMed

Substances