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CAR immune cells: design principles, resistance and the next generation

Author

Listed:
  • Louai Labanieh

    (Stanford University
    Stanford University
    Parker Institute for Cancer Immunotherapy)

  • Crystal L. Mackall

    (Stanford University
    Parker Institute for Cancer Immunotherapy
    Stanford University
    Stanford University)

Abstract

The remarkable clinical activity of chimeric antigen receptor (CAR) therapies in B cell and plasma cell malignancies has validated the use of this therapeutic class for liquid cancers, but resistance and limited access remain as barriers to broader application. Here we review the immunobiology and design principles of current prototype CARs and present emerging platforms that are anticipated to drive future clinical advances. The field is witnessing a rapid expansion of next-generation CAR immune cell technologies designed to enhance efficacy, safety and access. Substantial progress has been made in augmenting immune cell fitness, activating endogenous immunity, arming cells to resist suppression via the tumour microenvironment and developing approaches to modulate antigen density thresholds. Increasingly sophisticated multispecific, logic-gated and regulatable CARs display the potential to overcome resistance and increase safety. Early signs of progress with stealth, virus-free and in vivo gene delivery platforms provide potential paths for reduced costs and increased access of cell therapies in the future. The continuing clinical success of CAR T cells in liquid cancers is driving the development of increasingly sophisticated immune cell therapies that are poised to translate to treatments for solid cancers and non-malignant diseases in the coming years.

Suggested Citation

  • Louai Labanieh & Crystal L. Mackall, 2023. "CAR immune cells: design principles, resistance and the next generation," Nature, Nature, vol. 614(7949), pages 635-648, February.
    • Handle: RePEc:nat:nature:v:614:y:2023:i:7949:d:10.1038_s41586-023-05707-3
    DOI: 10.1038/s41586-023-05707-3
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    Cited by:

    1. Justin A. Guerrero & Dorota D. Klysz & Yiyun Chen & Meena Malipatlolla & Jameel Lone & Carley Fowler & Lucille Stuani & Audre May & Malek Bashti & Peng Xu & Jing Huang & Basil Michael & Kévin Contrepo, 2024. "GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Sameeha Jilani & Justin D. Saco & Edurne Mugarza & Aleida Pujol-Morcillo & Jeffrey Chokry & Clement Ng & Gabriel Abril-Rodriguez & David Berger-Manerio & Ami Pant & Jane Hu & Rubi Gupta & Agustin Vega, 2024. "CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Guillem Pascual-Pasto & Brendan McIntyre & Margaret G. Hines & Anna M. Giudice & Laura Garcia-Gerique & Jennifer Hoffmann & Pamela Mishra & Stephanie Matlaga & Simona Lombardi & Rawan Shraim & Patrick, 2024. "CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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