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Remote control of cellular immunotherapy

Nature Reviews Bioengineering volume 1, pages 440–455 (2023)Cite this article

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Abstract

Chimeric antigen receptor (CAR) T cell immunotherapy is emerging as a powerful tool for cancer treatment. However, the clinical application of CAR T cell therapy remains limited owing to on-target off-tumour toxicity and cytokine release syndrome, which can cause severe side effects. Remote and spatiotemporal control of CAR T cells could improve the safety and efficacy of CAR T cell therapy. Here, we discuss how CAR T cells can be externally controlled by combining stimuli-responsive nanotechnologies with immuno-engineering. We examine the use of different external stimuli, including light, ultrasound, magnetic fields, X-rays, electric fields and small molecules, to control the activity of CAR T cells against different malignancies and highlight the need for more efficient and biocompatible external stimuli as well as issues to be addressed to effectively treat solid tumours with CAR T cell therapy.

Key points

  • Chimeric antigen receptor (CAR) T cell therapies can be applied against various malignancies, with six CAR T cell therapies already approved by the FDA.

  • The clinical translation of CAR T cell immunotherapies, in particular against solid tumours, remains limited owing to low efficacy, potential cytotoxicity and considerable side effects, which may be addressed by precisely controlling the activation and antitumour effects of CAR T cells.

  • The combination of nanotechnologies and nano-optogenetic, chemogenetic and immuno-engineering approaches allows the remote control of CAR T cell therapies, using various external stimuli, including light, ultrasound, small molecules, magnetic energy, X-rays and electric fields.

  • Remote control strategies may prove particularly useful for the treatment of solid tumours, which are currently not susceptible to CAR T cell therapy.

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Fig. 1: CAR T cell-based immunotherapy and external stimuli.
Fig. 2: Light-induced and photothermally induced CAR T cell therapy.
Fig. 3: Ultrasound-stimulated and magnetic field-stimulated CAR T cell therapy.
Fig. 4: Chemogenetic control of CAR T cell therapy.

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Acknowledgements

This work was supported by the National Institutes of Health (R01CA232017 to G.H. and Y.Z., R01CA240258 to Y.H., R01GM144986 to Y.Z., and R01EB029122 and R35GM140929 to Y. W.), the Welch Foundation (BE-1913-20220331 to Y.Z.) and the Cancer Prevention and Research Institutes of Texas (RP210070 to Y.Z.). The authors apologize to those whose primary work has not been cited here for lack of space.

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  1. These authors contributed equally: Kai Huang, Yubin Zhou.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Kai Huang & Gang Han

  2. ShuChien-Gene Lay Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, CA, USA

    Longwei Liu & Yingxiao Wang

  3. Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA

    Yun Huang & Yubin Zhou

  4. Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA

    Yubin Zhou

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G.H., Y.Z. and Y.W. conceived the idea and supervised the work. K.H., Y.H., Y.Z. and G.H. drafted the initial manuscript with inputs and further editing from all other authors.

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Correspondence to Yingxiao Wang, Yubin Zhou or Gang Han.

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Y.W. is a scientific co-founder of Cell E&G and Acoustic Cell Therapy. These financial interests do not affect the design, conduct or reporting of this research. The other authors declare no competing interests.

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Huang, K., Liu, L., Huang, Y. et al. Remote control of cellular immunotherapy. Nat Rev Bioeng 1, 440–455 (2023). https://doi.org/10.1038/s44222-023-00042-8

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