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  • Review Article
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Advancing CAR T cell therapy through the use of multidimensional omics data

Nature Reviews Clinical Oncology volume 20, pages 211–228 (2023)Cite this article

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Abstract

Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of certain haematological malignancies, challenges remain in optimizing CAR designs and cell products, improving response rates, extending the durability of remissions, reducing toxicity and broadening the utility of this therapeutic modality to other cancer types. Data from multidimensional omics analyses, including genomics, epigenomics, transcriptomics, T cell receptor-repertoire profiling, proteomics, metabolomics and/or microbiomics, provide unique opportunities to dissect the complex and dynamic multifactorial phenotypes, processes and responses of CAR T cells as well as to discover novel tumour targets and pathways of resistance. In this Review, we summarize the multidimensional cellular and molecular profiling technologies that have been used to advance our mechanistic understanding of CAR T cell therapies. In addition, we discuss current applications and potential strategies leveraging multi-omics data to identify optimal target antigens and other molecular features that could be exploited to enhance the antitumour activity and minimize the toxicity of CAR T cell therapy. Indeed, fully utilizing multi-omics data will provide new insights into the biology of CAR T cell therapy, further accelerate the development of products with improved efficacy and safety profiles, and enable clinicians to better predict and monitor patient responses.

Key points

  • Multidimensional omics data, encompassing genomics, epigenomics, transcriptomics, T cell receptor-repertoire profiling, proteomics, metabolomics and microbiomics, have been exploited to advance our mechanistic understanding of chimeric antigen receptor (CAR) T cell therapy.

  • Utilization of multi-omics data derived from both tumour and non-malignant tissues at the bulk and/or single-cell levels is a powerful approach to identifying optimal targets for highly efficacious and safe CAR T cell therapy.

  • Integration of bulk and/or single-cell multidimensional omics data has been applied to investigate key determinants of CAR T cell persistence and antitumour efficacy, including T cell states and phenotypes, tumour cell characteristics, the tumour microenvironment and the microbiome.

  • Leveraging multi-omics data promises to elucidate the mechanisms underlying CAR T cell-related toxicities, including cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome and on-target, off-tumour toxicities.

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Fig. 1: Overview of applications of multi-omics data in CAR T cell therapy.
Fig. 2: Applications of multi-omics data in CAR target identification.
Fig. 3: Multidimensional omics characterization of molecular features associated with the efficacy of CAR T cell therapy.
Fig. 4: Summary of factors related to major categories of CAR T cell-induced toxicities revealed by multi-omics data.

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Acknowledgements

The work of the authors is supported by the US NIH (grants R01HG011633 and R01CA262623 to L.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. M.R.G. is a Scholar of the Leukaemia and Lymphoma Society. The authors regret that page limitations have prevented them from including all the relevant studies in this Review. Draft figures for this manuscript were created with BioRender.com.

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Author notes

  1. These authors contributed equally: Jingwen Yang, Yamei Chen, Ying Jing.

Authors and Affiliations

  1. Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA

    Jingwen Yang, Yamei Chen & Leng Han

  2. Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA

    Ying Jing

  3. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael R. Green

  4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael R. Green

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

    Leng Han

Authors
  1. Jingwen Yang
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  2. Yamei Chen
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  3. Ying Jing
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  4. Michael R. Green
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  5. Leng Han
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Contributions

All authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding authors

Correspondence to Michael R. Green or Leng Han.

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Competing interests

M.R.G. has stock ownership interest in KDAc Therapeutics, receives funding from Abbvie, Allogene, Kite/Gilead and Sanofi, and has received honoraria from Tessa Therapeutics. J.Y., Y.C., Y.J. and L.H. declare no competing interests.

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Peer review information

Nature Reviews Clinical Oncology thanks M. Maus, who co-reviewed with N. Haradhvala; R. Fan, who co-reviewed with Z. Bai; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Antigen Explorer: https://antigen.princeton.edu/

CARTSC: https://hanlab.tamhsc.edu/CARTSC/

ClinicalTrials.gov: https://clinicaltrials.gov/ct2/home

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Yang, J., Chen, Y., Jing, Y. et al. Advancing CAR T cell therapy through the use of multidimensional omics data. Nat Rev Clin Oncol 20, 211–228 (2023). https://doi.org/10.1038/s41571-023-00729-2

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