Skip to main page content
U.S. flag
See More

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
. 2020 Jul 2;13(1):86.
doi: 10.1186/s13045-020-00910-5.

Recent advances in CAR-T cell engineering

Ruihao Huang  1 , Xiaoping Li  1 , Yundi He  1 , Wen Zhu  1 , Lei Gao  1 , Yao Liu  1 , Li Gao  1 , Qin Wen  1 , Jiang F Zhong  2 , Cheng Zhang  3 , Xi Zhang  4
Affiliations
Review

Recent advances in CAR-T cell engineering

Ruihao Huang et al. J Hematol Oncol. .

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. Although the initially approved anti-CD19 CAR-T therapy has produced impressive outcomes, setbacks such as high relapse rates and resistance were experienced, driving the need to discover engineered CAR-T cells that are more effective for therapeutic use. Innovations in the structure and manufacturing of CAR-T cells have resulted in significant improvements in efficacy and persistence, particularly with the development of fourth-generation CAR-T cells. Paired with an immune modifier, the use of fourth-generation and next-generation CAR-T cells will not be limited because of cytotoxic effects and will be an efficient tool for overcoming the tumor microenvironment. In this review, we summarize the recent transformations in the ectodomain, transmembrane domain, and endodomain of the CAR structure, which, together with innovative manufacturing technology and improved cell sources, improve the prospects for the future development of CAR-T cell therapy.

Keywords: CAR-T cell therapy; Hematological malignancies; Immune therapy.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Innovation orientation and goals for transforming CAR-T cell engineering. Each cell in the inner rings with black letters represents an orientation of CAR-T cell transformation. The emerging benefits are shown in the outer rings with white letters. Clearly, in addition to improving the efficacy, the bulk of these endeavors consists of identifying the appropriate targets of the ectodomain and improving manufacturing to increase the efficacy of CAR-T cell therapy toward more diseases and ensure that is faster, safer, and more economical to satisfy more patients’ needs. After discovering the vital role of a costimulation domain choice, the importance of the transmembrane and hinge domains, as recently discovered, must be considered, as these choices affect binding and active signal transduction. As shown in this figure, substantial efforts have been devoted to develop fourth-generation and next-generation CAR-T cells. Additional areas of research were added to overcome the TME (one of the major causes of resistance to traditional CAR-T cell therapy, particularly in solid tumors). Fourth-generation and next-generation CAR-T cells are an effective tool to reconstruct the immune system of patients after the elimination of tumor cells
Fig. 2
Fig. 2
The antitumor mechanisms of fourth-generation and next-generation CAR-T cells. With the aid of transduced cytokines and the agonist of the T cell receptor, CAR-T cells self-activate through autocrine and paracrine mechanisms and stimulate host T cells to regain antitumor efficacy. In addition, blockade of the inhibitory receptor prevents the apoptosis induced by receptors such as PD-1, which reconstructs the host immune system. Furthermore, a BiTE facilitates CAR-T cell and host T cell infiltration into tumor sites and the interaction between T cells and tumor cells. For tumors with a strong TME, artificially transduced CXCRs guide CAR-T cells to the tumor and express chemokines at high levels, a key method by which the tumor modulates other immune cells and forms the TME. Last but not least, we illustrate switch receptors, which are assembled from the extracellular domain of the inhibitory receptor and the intracellular domain of the activating receptor
See this image and copyright information in PMC

References

    1. Liu D. CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy. J Hematol Oncol. 2019;12:113. - PMC - PubMed
    1. Schuster SJ. CD19-directed CAR T cells gain traction. Lancet Oncol. 2019;20:2–3. - PubMed
    1. Zhang L-N, Song Y, Liu D. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. J Hematol Oncol. 2018;11:41. - PMC - PubMed
    1. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, 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;20:31–42. - PMC - PubMed
    1. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45–56. - PubMed

Publication types

MeSH terms

LinkOut - more resources