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  • Perspective
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Engineering immune-evasive allogeneic cellular immunotherapies

Nature Reviews Immunology (2024)Cite this article

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Abstract

Allogeneic cellular immunotherapies hold a great promise for cancer treatment owing to their potential cost-effectiveness, scalability and on-demand availability. However, immune rejection of adoptively transferred allogeneic T and natural killer (NK) cells is a substantial obstacle to achieving clinical responses that are comparable to responses obtained with current autologous chimeric antigen receptor T cell therapies. In this Perspective, we discuss strategies to confer cell-intrinsic, immune-evasive properties to allogeneic T cells and NK cells in order to prevent or delay their immune rejection, thereby widening the therapeutic window. We discuss how common viral and cancer immune escape mechanisms can serve as a blueprint for improving the persistence of off-the-shelf allogeneic cell therapies. The prospects of harnessing genome editing and synthetic biology to design cell-based precision immunotherapies extend beyond programming target specificities and require careful consideration of innate and adaptive responses in the recipient that may curtail the biodistribution, in vivo expansion and persistence of cellular therapeutics.

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Fig. 1: Mechanisms of T cell- and NK cell-mediated allorejection.
Fig. 2: Challenges in the clinical translation of allogeneic ACT.
Fig. 3: Engineered immune evasion strategies in allogeneic ACTs.

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Acknowledgements

This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement number 8382909 (to Q.H.). This work was supported by the Swedish Research Council, the Swedish Children’s Cancer Society (PR2020-1059), the Swedish Cancer Society (21-1793Pj), Sweden’s Innovation Agency and the Karolinska Institutet. The work was further supported by the Research Council of Norway (275469, 237579), Center of Excellence: Precision Immunotherapy Alliance (332727), the Norwegian Cancer Society (190386, 223310), the South-Eastern Norway Regional Health Authority (2024-053), EU H2020-MSCA Research and Innovation programme (801133), Knut and Alice Wallenberg Foundation, Swedish Foundation for Strategic Research, the US National Cancer Institute (P01 CA111412, P009500901, all to K.-J.M.) and NCI Cancer Center Support Grant number P30 CA008748 (to M.S.). The authors thank P. Ljungman for the helpful discussions. The language model GPT-4 was used to check the text for correct grammar.

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  1. These authors contributed equally: Karen E. Martin, Quirin Hammer, Karlo Perica.

Authors and Affiliations

  1. Precision Immunotherapy Alliance, The University of Oslo, Oslo, Norway

    Karen E. Martin & Karl-Johan Malmberg

  2. Department of Cancer Immunology, Institute for Cancer Research Oslo, Oslo University Hospital, Oslo, Norway

    Karen E. Martin & Karl-Johan Malmberg

  3. Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden

    Quirin Hammer & Karl-Johan Malmberg

  4. Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Karlo Perica & Michel Sadelain

  5. Cell Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Karlo Perica

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K.-J.M. is a consultant at Fate Therapeutics. K.-J.M. has research support from Oncopeptides. K.-J.M. and Q.H. are consultants at Vycellix. All relationships have been approved by Oslo University Hospital, University of Oslo and Karolinska Institute. M.S. receives research support (for unrelated studies) from Fate Therapeutics and Takeda.

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Martin, K.E., Hammer, Q., Perica, K. et al. Engineering immune-evasive allogeneic cellular immunotherapies. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01022-8

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