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Genetic engineering of T cells for immunotherapy

Abstract

Genetically engineered T cell immunotherapies have provided remarkable clinical success to treat B cell acute lymphoblastic leukaemia by harnessing a patient’s own T cells to kill cancer, and these approaches have the potential to provide therapeutic benefit for numerous other cancers, infectious diseases and autoimmunity. By introduction of either a transgenic T cell receptor or a chimeric antigen receptor, T cells can be programmed to target cancer cells. However, initial studies have made it clear that the field will need to implement more complex levels of genetic regulation of engineered T cells to ensure both safety and efficacy. Here, we review the principles by which our knowledge of genetics and genome engineering will drive the next generation of adoptive T cell therapies.

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Fig. 1: Autologous and allogeneic T cell immunotherapy.
Fig. 2: The genetic outcome of modifying the T cell genome.
Fig. 3: Gene-engineered T cell products to enhance efficacy.
Fig. 4: Addition of armour or subtraction of suppressive genes or their transcripts enables TME resistance.
Fig. 5: Toxicity risks associated with gene-engineered T cells.
Fig. 6: Gene-engineered T cell products for enhanced safety.

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Acknowledgements

The authors are grateful to the members of the Center for Cellular Immunotherapies for in-depth discussions regarding the topics discussed in this Review and apologize to the many investigators whose work they were unable to cite. The authors gratefully acknowledge funding from the NIH (U19AI117950, U19AI149680 UM1AI126620 and UG3DK122644), Helmsley Charitable Trust and Tmunity Therapeutics.

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The authors contributed equally to all aspects of the article.

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Correspondence to James L. Riley.

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Competing interests

J.L.R. is a co-founder and shareholder of Tmunity Therapeutics. He has been in receipt of research funding from Tmunity Therapeutics. N.C.S. is a shareholder of Tmunity Therapeutics and Fate Therapeutics. G.I.E. declares no competing interests.

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Nature Reviews Genetics thanks M. K. Levings, Z. Li, E. L. Smith, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

NCT01236573: https://clinicaltrials.gov/ct2/show/NCT01236573

NCT03240328: https://clinicaltrials.gov/ct2/show/NCT03240328

NCT03617198: https://clinicaltrials.gov/ct2/show/NCT03617198

NCT04422912: https://clinicaltrials.gov/ct2/show/NCT04422912

Glossary

Allogeneic

A term to denote a genetically different individual of the same species.

Antigen loss

A mechanism of cancer or pathogen recurrence in which the target (tumour or pathogen) escapes engineered T cell recognition, typically via exon skipping, downregulation or alteration of the target antigen.

Epitope spreading

Diversification of the immune response by endogenous immune cells against new targets following engineered T cell therapy.

Boolean logic gate

AND, OR and NOT functions, which can describe the response of combinations of immune receptors to multiple antigens.

Immune synapse

The location of physical interaction between an immune cell and its activator, either another immune cell or a non-haematopoietic target cell. The strength and the type of signals exchanged at the immune synapse can modulate an immune response.

Single-chain variable fragment

(scFv). A linear transposition of an antibody’s heavy and light chains separated by a flexible linker, which retains the antigen binding capacity of the original antibody and can be used as the binder domain of a chimeric antigen receptor molecule.

Monoclonal antibodies

(mAbs). Antibodies purified from a single B cell hybridoma that can be used as a diagnostic or therapeutic product.

Fc-dependent mechanisms

A series of effector modalities by which targets bound by antibodies are depleted via recognition of the constant region of the antibody molecule.

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Ellis, G.I., Sheppard, N.C. & Riley, J.L. Genetic engineering of T cells for immunotherapy. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-021-00329-9

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