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Delivery technologies to engineer natural killer cells for cancer immunotherapy

Abstract

In recent years, immune cell-based cancer therapeutics have been utilized broadly in the clinic. Through advances in cellular engineering, chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial success in treating hematological tumors and have become the most prominent cell-based therapy with three commercialized products in the market. However, T-cell-based immunotherapies have certain limitations, including a restriction to autologous cell sources to avoid severe side-effects caused by human leukocyte antigen (HLA) mismatch. This necessity for personalized treatment inevitably results in tremendous manufacturing and time costs, reducing accessibility for many patients. As an alternative strategy, natural killer (NK) cells have emerged as potential candidates for improved cell-based immunotherapies. NK cells are capable of killing cancer cells directly without requiring HLA matching. Furthermore, NK cell-based therapies can use various allogeneic cell sources, allowing for the possibility of “off-the-shelf” immunotherapies with reduced side-effects and shortened manufacturing times. Here we provide an overview of the use of NK cells in cancer immunotherapy, their current status in clinical trials, as well as the design and implementation of delivery technologies—including viral, non-viral, and nanoparticle-based approaches—for engineering NK cell-based immunotherapies.

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Fig. 1: Delivery technologies for engineering natural killer (NK) cells.
Fig. 2: Natural killer (NK) cell subsets and cytotoxic mechanisms.
Fig. 3: Functional delivery of mRNA by charge-altering releasable transports (CARTs).
Fig. 4: Ionizable lipid nanoparticle (LNP)-mediated delivery of CAR mRNA for CAR T-cell engineering.
Fig. 5: “Super” natural killer (NK) cell formation.
Fig. 6: Glycoengineering NK-92 cells with CD22 ligands for effective targeting and lysis of CD22-positive cancer cells.
Fig. 7: Schematic of target-specific aptamers anchored on the surface of NK cells forming aptamer-engineered NK (ApEn-NK) cells.

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Acknowledgements

M.J.M. acknowledges support from a U.S. National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776), a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), the National Institutes of Health (NCI R01 CA241661, NCI R37 CA244911, and NIDDK R01 DK123049), an Abramson Cancer Center (ACC)-School of Engineering and Applied Sciences (SEAS) Discovery Grant (P30 CA016520), and a 2018 AACR-Bayer Innovation and Discovery Grant, Grant Number 18-80- 44-MITC (to M.J.M.). A.G.H. is supported by a National Science Foundation (NSF) Graduate Research Fellowship (DGE 1845298).

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R.E., Z.Z., A.G.H., and M.J.M. conceived the ideas, researched the data for the manuscript, discussed the manuscript content, and wrote the manuscript. Z.Z. designed the display items. All authors reviewed and edited the article before submission.

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Correspondence to Michael J. Mitchell.

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El-Mayta, R., Zhang, Z., Hamilton, A.G. et al. Delivery technologies to engineer natural killer cells for cancer immunotherapy. Cancer Gene Ther 28, 947–959 (2021). https://doi.org/10.1038/s41417-021-00336-2

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