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Prospects for gene-engineered T cell immunotherapy for solid cancers

Abstract

Adoptive transfer of receptor-engineered T cells has produced impressive results in treating patients with B cell leukemias and lymphomas. This success has captured public imagination and driven academic and industrial researchers to develop similar 'off-the-shelf' receptors targeting shared antigens on epithelial cancers, the leading cause of cancer-related deaths. However, the successful treatment of large numbers of people with solid cancers using this strategy is unlikely to be straightforward. Receptor-engineered T cells have the potential to cause lethal toxicity from on-target recognition of normal tissues, and there is a paucity of truly tumor-specific antigens shared across tumor types. Here we offer our perspective on how expanding the use of genetically redirected T cells to treat the majority of patients with solid cancers will require major technical, manufacturing and regulatory innovations centered around the development of autologous gene therapies targeting private somatic mutations.

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Figure 1: CAR and TCR clinical trials for oncology indications in the US between 1994 and 2014.
Figure 2: Safety and tissue-selectivity mechanisms that may be inserted into gene-engineered T cells.
Figure 3: A pathway for generating autologous TCR gene therapies targeting neoantigens for patients with advanced epithelial cancers.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US National Institutes of Health (NIH) (ZIA BC011586 and ZIA BC010763) and the NIH Center for Regenerative Medicine. Additional support was provided by generous gifts from L. Jinyuan of the Tiens Charitable Foundation and the Milstein Family Foundation.

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C.A.K., S.A.R. and N.P.R. wrote and revised the manuscript.

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Correspondence to Christopher A Klebanoff or Nicholas P Restifo.

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S.A.R. reports receiving research support in the form of Cooperative Research and Development Agreements (CRADAs) with KITE Pharma, Lion Biotechnologies and Intrexon; C.A.K. and N.P.R. report no conflicts of interest.

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Klebanoff, C., Rosenberg, S. & Restifo, N. Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22, 26–36 (2016). https://doi.org/10.1038/nm.4015

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