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Review
. 2022 Mar 18:13:822298.
doi: 10.3389/fimmu.2022.822298. eCollection 2022.

Taking Lessons from CAR-T Cells and Going Beyond: Tailoring Design and Signaling for CAR-NK Cells in Cancer Therapy

Affiliations
Review

Taking Lessons from CAR-T Cells and Going Beyond: Tailoring Design and Signaling for CAR-NK Cells in Cancer Therapy

Katharina Eva Ruppel et al. Front Immunol. .

Abstract

Cancer immunotherapies utilize the capabilities of the immune system to efficiently target malignant cells. In recent years, chimeric antigen receptor (CAR) equipped T cells showed promising results against B cell lymphomas. Autologous CAR-T cells require patient-specific manufacturing and thus extensive production facilities, resulting in high priced therapies. Along with potentially severe side effects, these are the major drawbacks of CAR-T cells therapies. Natural Killer (NK) cells pose an alternative for CAR equipped immune cells. Since NK cells can be safely transferred from healthy donors to cancer patients, they present a suitable platform for an allogeneic "off-the-shelf" immunotherapy. However, administration of activated NK cells in cancer therapy has until now shown poor anti-cancer responses, especially in solid tumors. Genetic modifications such as CARs promise to enhance recognition of tumor cells, thereby increasing anti-tumor effects and improving clinical efficacy. Although the cell biology of T and NK cells deviates in many aspects, the development of CAR-NK cells frequently follows within the footsteps of CAR-T cells, meaning that T cell technologies are simply adopted to NK cells. In this review, we underline the unique properties of NK cells and their potential in CAR therapies. First, we summarize the characteristics of NK cell biology with a focus on signaling, a fine-tuned interaction of activating and inhibitory receptors. We then discuss why tailored NK cell-specific CAR designs promise superior efficacy compared to designs developed for T cells. We summarize current findings and developments in the CAR-NK landscape: different CAR formats and modifications to optimize signaling, to target a broader pool of antigens or to increase in vivo persistence. Finally, we address challenges beyond NK cell engineering, including expansion and manufacturing, that need to be addressed to pave the way for CAR-NK therapies from the bench to the clinics.

Keywords: CAR-NK cell; CAR-T cells; NK cell receptors and ligands; allogenic cell therapy; cell signaling; chimeric antigen receptor (CAR); gene therapy; immunotherapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of NK cell receptors and their signaling adapters. Inhibitory receptors are situated on the left (violet membrane), receptors with activating and inhibitory signaling motifs central (orange membrane) and activating receptors on the right (green membrane). ITAM, immunoreceptor tyrosine-based activation motif; hemITAM, hemi-immunoreceptor tyrosine-based activation motif; ITSM, immunoreceptor tyrosine based switch motifs; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITT, immunoglobulin tail tyrosine.
Figure 2
Figure 2
Different CAR formats. Upper left: 2nd generation CAR format that is approved on the market for T cells. Other CAR designs improve signaling for NK cells, couple CAR expression and activation to transcription factor systems, target a broader pool of antigens or aim to overcome inhibitory signals of the tumor immunosuppressive environment. TF, Transcription factor; aCAR, activating CAR; iCAR, inhibitory CAR.

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References

    1. Fischer JW, Bhattarai N. CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities. Front Immunol (2021) 12:693016. doi: 10.3389/fimmu.2021.693016 - DOI - PMC - PubMed
    1. Vucinic V, Quaiser A, Lückemeier P, Fricke S, Platzbecker U, Koehl U. Production and Application of CAR T Cells: Current and Future Role of Europe. Front Med (2021) 8:713401. doi: 10.3389/fmed.2021.713401 - DOI - PMC - PubMed
    1. Guedan S, Calderon H, Posey AD, Jr, Maus MV. Engineering and Design of Chimeric Antigen Receptors. Mol Ther Methods Clin Dev (2019) 12:145–56. doi: 10.1016/j.omtm.2018.12.009 - DOI - PMC - PubMed
    1. Marofi F, Motavalli R, Safonov VA, Thangavelu L, Yumashev AV, Alexander M, et al. . CAR T Cells in Solid Tumors: Challenges and Opportunities. Stem Cell Res Ther (2021) 12:81. doi: 10.1186/s13287-020-02128-1 - DOI - PMC - PubMed
    1. Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, et al. . Induction of Resistance to Chimeric Antigen Receptor T Cell Therapy by Transduction of a Single Leukemic B Cell. Nat Med (2018) 24:1499–503. doi: 10.1038/s41591-018-0201-9 - DOI - PMC - PubMed

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