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Genetically engineered hypoimmunogenic cell therapy

Nature Reviews Bioengineering (2024)Cite this article

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Abstract

Immune rejection is an important obstacle to the use of allogeneic ‘off-the-shelf’ cells for transplantation into immunocompetent patients. Genetic modification has emerged as a promising approach to improve immune compatibility in various applications, including cancer immunotherapy and stem cell-based therapies. Several approaches have been proposed to evade the recognition and attack of transplanted cells by specific host immune cells; however, further investigation is needed to ensure the hypoimmunity and safety of cell-based therapies in clinical practice. This Review discusses key advances and challenges in the clinical translation of hypoimmunogenic cells and describes the genetic engineering methods and manufacturing processes used to create hypoimmunogenic therapeutic cells, while highlighting the complexity of relevant immunological pathways.

Key points

  • Hypoimmunogenic cells created through genetic engineering are likely to become a mainstream approach to allogeneic cell therapy that can avoid or mitigate the need for immunosuppression in treated patients.

  • Immune rejection of allogeneic cell-based clinical therapies can be avoided by the removal of antigens and/or the expression of immunosuppressive factors.

  • The potential risk of tumorigenesis can be mitigated by careful quality assessment and incorporation of a safety ‘kill switch’ into engineered cells.

  • To establish a successful hypoimmunogenic cell therapy, it is important to consider multiple factors, including which cell types to utilize, target genes, editing methods, quality control mechanisms and host-related factors.

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Fig. 1: HLA gene variations and biallelic HLA haplotype matching.
Fig. 2: HLA-knockout approaches that facilitate HLA matching.
Fig. 3: Hypoimmunogenic engineering approaches, target cell types and molecules.

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Acknowledgements

The authors thank K. Hui and F. Nakamura for critically reading the manuscript. The authors’ research work is supported by the Japan Agency for Medical Research and Development (AMED) grant numbers JP22bm1123006 and JP23bm1323001 to A.H., and by the Canadian Institutes of Health Research (CIHR) Foundation grants, Canadian Research Chair, Ontario Research Fund and Medicine by Design (University of Toronto) funding to A.N.

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Authors and Affiliations

  1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan

    Akitsu Hotta

  2. Sana Biotechnology, South San Francisco, CA, USA

    Sonja Schrepfer

  3. Lunenfeld–Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Andras Nagy

  4. Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia

    Andras Nagy

  5. Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada

    Andras Nagy

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A.H. initiated the project. All authors contributed to all aspects of the article (researching data, writing, and reviewing and/or editing the manuscript).

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Correspondence to Akitsu Hotta.

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Competing interests

A.H. declares that he has acted as a scientific advisor for AstraZeneca, CiRA Foundation, Orizuru Therapeutics and Takeda Pharmaceuticals. S.S. declares that she is a scientific founder, employee and stockholder of Sana Biotechnology. A.N. declares that he is a co-founder of panCELLa.

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Hotta, A., Schrepfer, S. & Nagy, A. Genetically engineered hypoimmunogenic cell therapy. Nat Rev Bioeng (2024). https://doi.org/10.1038/s44222-024-00219-9

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