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
. 2021 May 19:15:175-198.
doi: 10.2147/BTT.S252568. eCollection 2021.

How Can We Engineer CAR T Cells to Overcome Resistance?

Maya Glover  1 , Stephanie Avraamides  2 , John Maher  1   2   3   4
Affiliations
Review

How Can We Engineer CAR T Cells to Overcome Resistance?

Maya Glover et al. Biologics. .

Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved unrivalled success in the treatment of B cell and plasma cell malignancies, with five CAR T cell products now approved by the US Food and Drug Administration (FDA). However, CAR T cell therapies for solid tumours have not been nearly as successful, owing to several additional challenges. Here, we discuss mechanisms of tumour resistance in CAR T cell therapy and the emerging strategies that are under development to engineer CAR T cells to overcome resistance.

Keywords: T-cell; cancer; chimeric antigen receptor; immunotherapy; resistance.

PubMed Disclaimer

Conflict of interest statement

JM is founder, chief scientific officer and shareholder in Leucid Bio. MG is an employee and shareholder in Leucid Bio. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
High level overview of strategies to engineer resistance in CAR T-cells. Tumour resistance to CAR T cell therapy can be overcome by (A) improving CAR T cell fitness to enhance proliferation, persistence and cytotoxicity; (B) engineering CAR T cells to resist the suppressive TME including checkpoint inhibitors, immunosuppressive cells and cytokines and the tumour stroma, whilst enhancing tumour homing and infiltration; (C) Engineering CAR T cells to overcome tumour resistance caused by antigen loss or downregulation by promoting epitope spreading, targeting multiple antigens or introducing artificial ligands to the tumour.
Figure 2
Figure 2
Structural components of CAR T cells. The structure of a first generation CAR consists of an antigen binding domain attached to a transmembrane domain via a hinge/spacer, followed by a CD3ξ signalling domain. Second generation CARs have an additional co-stimulatory domain and third generation CARs contain two co-stimulatory domains. Fourth generation CARs are armoured to secrete cytokines. All structural components of CAR T cells illustrated can be refined to enhance function.
Figure 3
Figure 3
Structure of CARs to target multiple antigens. Tumour antigen loss can be overcome by targeting multiple antigens by various CAR T cell structures. Dual CAR T cells contain two distinct 2G CARs expressed on a single cell which recognise two different target antigens. Trivalent CAR T cells contain three distinct CARs able to recognise three different target antigens. Tandem CARs contain two distinct scFvs fused together by a flexible linker. Universal CARs consist of universal receptor and an antigen binding adaptor molecule, of which different target binders can be utilised.
See this image and copyright information in PMC

References

    1. Kuwana Y, Asakura Y, Utsunomiya N, et al. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun. 1987;149(3):960–968. doi: 10.1016/0006-291X(87)90502-X - DOI - PubMed
    1. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993;90(2):720–724. doi: 10.1073/pnas.90.2.720 - DOI - PMC - PubMed
    1. Finney HM, Lawson AD, Bebbington CR, Weir AN. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol. 1998;161(6):2791–2797. - PubMed
    1. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20(1):31–42. doi: 10.1016/S1470-2045(18)30864-7 - DOI - PMC - PubMed
    1. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. - PubMed