Chimeric antigen receptor–engineered natural killer and natural killer T cells for cancer immunotherapy

  • Dominique Bollino
    Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, Md
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  • Tonya J. Webb
    Reprint requests: Tonya J. Webb, 685 West Baltimore Street HSF1, Rm 380, Baltimore, MD 21201
    Department of Microbiology and Immunology, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, Baltimore, Md
    Search for articles by this author
      Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte subsets that have similarities in their functions and phenotypes. Both cell types can rapidly respond to the presence of tumor cells and participate in immune surveillance and antitumor immune responses. This has incited interest in the development of novel cancer therapeutics based on NK and NKT cell manipulation. Chimeric antigen receptors (CARs), generated through the fusion of an antigen-binding region of a monoclonal antibody or other ligand to intracellular signaling domains, can enhance lymphocyte targeting and activation toward diverse malignancies. Most of the CAR studies have focused on their expression in T cells; however, the functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. CAR-modified NK and NKT cells are becoming more prevalent because they provide a method to direct these cells more specifically to target cancer cells, with less risk of adverse effects. This review will outline current NK and NKT cell CAR constructs and how they compare to conventional CAR T cells, and discuss future modifications that can be explored to advance adoptive cell transfer of NK and NKT cells.


      aAPC (artificial antigen-presenting cells), αGalCer (α-galactosylceramide), ACT (adoptive cell transfer), ADCC (antibody-dependent cell-mediated cytotoxicity), ALL (Acute Lymphoblastic Leukemia), AML (acute lymphoid leukemia), CAR (chimeric antigen receptor), CRS (cytokine release syndrome), DC (dendritic cell), GM-CSF (granulocyte macrophage colony stimulating factor), GVHD (graft versus host disease), HLA (human leukocyte antigen), iPSC (induced pluripotent stem cells), KIR (killer immunoglobulin-like receptors), MHC (major histocompatibility complex), NCR (natural cytotoxicity receptors), NK (Natural Killer), NKT (Natural Killer T), scFv (single-chain variable fragment), TAM (tumor-associated macrophage), TCR (T cell receptor), TGF-β (transforming growth factor-β), TME (tumor microenvironment), TNF (tumor necrosis factor), TRAIL (TNF-related apoptosis-inducing ligand)
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