Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV

Abstract

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body’s immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.

Challenges of NK cell-based immunotherapy in the new era

“…Transfection efficiency for primary NK cells particularly remains the bottleneck. The transduction efficiency can reach approximately 70% in retroviruses in T cells [29], 15%-40% in NK cell lines [100], less than 20% in primary NK cells, and 6%-96% in ex vivo expanded NK cells [101]. Transiently inhibiting the antiviral defense signaling pathway leads to remarkably increased virus transduction efficiency, but it is not practical for the large-scale manufacture of CAR-NK cells [102].…”

Current strategies exploiting NK‐cell therapy to treat haematologic malignancies

“…Recently, Chimeric antigen receptors (CARs) on NK cells have been used to direct NK‐cell antitumour activity. In a recent study, cord‐blood‐derived NK cells were transduced with a retroviral vector incorporating CAR‐CD19, IL‐15 and inducible caspase‐9 suicide (iC9) gene (Liu et al, ). This CAR‐NK cell incorporates CD19 to redirect NK‐cell specificity, IL‐15 so that they can sustain their growth, and iC9 so that the CAR‐NK cell can be eliminated.…”

“…Recently, Chimeric antigen receptors (CARs) on NK cells have been used to direct NK-cell antitumour activity. In a recent study, cordblood-derived NK cells were transduced with a retroviral vector incorporating CAR-CD19, IL-15 and inducible caspase-9 suicide (iC9) gene (Liu et al, 2017 (Romagné et al, 2009; Figure 1). Phase I clinical trials showed that this antibody is tolerated by AML and MM patients and that it led to enhanced cytotoxic activity (Benson et al, 2011(Benson et al, , 2015Vey et al, 2012).…”

Natural killer cell immunotherapy against multiple myeloma: Progress and possibilities

“…62,63 Activated NK-92-CS1-CAR cells are detected to highly secret IFN-, perforin, and granzyme B, and they significantly express CD69 and HLA-DR. 17 In comparison with CAR-T cells, CAR-NK cells show safety and effectiveness. 64 CAR-NK cells have more functional NK cell lines, NK92 cell line is widely applied in clinical trials. 65 In addition, T cells- ADCC-mediated killing.…”