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  • Review Article
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Developing neoantigen-targeted T cell–based treatments for solid tumors

Abstract

Stimulating an immune response against cancer through adoptive transfer of tumor-targeting lymphocytes has shown great promise in hematological malignancies, but clinical efficacy against many common solid epithelial cancers remains low. Targeting ‘neoantigens’—the somatic mutations expressed only by tumor cells—might enable tumor destruction without causing undue damage to vital healthy tissues. Major challenges to targeting neoantigens with T cells include heterogeneity and variability in antigen processing and presentation of targets by tumors, and an incomplete understanding of which T cell qualities are essential for clinically effective therapies. Finally, the prospect of targeting somatic tumor mutations to promote T cell destruction of cancer must contend with the biology that not all tumor-expressed ‘neoepitopes’ actually generate neoantigens that can be functionally recognized and provoke an effective immune response. In this Review, we discuss the promise, progress and challenges for improving neoantigen-targeted T cell–based immunotherapies for cancer.

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Fig. 1: Current methodology to identify and expand neoantigen-reactive TIL.
Fig. 2: Difficulties encountered during neoantigen-reactive T cell identification.
Fig. 3: Categorizing the heterogeneous nature of patient tumors.
Fig. 4: Proposed mechanisms demonstrating protection provided by cell-intrinsic Fas blockade.
Fig. 5: Combinatorial approaches to generate the ultimate personalized T cell therapy.

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Acknowledgements

We thank P.-H. Lee for helpful discussions and E. He for illustration design. This work was supported by the Intramural Research Program of the NCI and the Cancer Moonshot Program for the Center for Cell-Based Therapy at the NCI, NIH.

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Correspondence to Nicholas P. Restifo.

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N.P.R. is currently employed by and holds equity in Lyell Immunopharma.

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Yamamoto, T.N., Kishton, R.J. & Restifo, N.P. Developing neoantigen-targeted T cell–based treatments for solid tumors. Nat Med 25, 1488–1499 (2019). https://doi.org/10.1038/s41591-019-0596-y

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