Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

Abstract

Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples. Human primary NK cells and the NK-92 cell line have been successfully transduced to express CARs against both hematological cancers and solid tumors in pre-clinical and clinical trials. However, many challenges and obstacles remain, such as the ex vivo expansion of CAR-modified primary NK cells and the low transduction efficiency of NK cells. Many strategies and technologies have been developed to improve the safety and therapeutic efficacy in CAR-based immunotherapy. Moreover, NK cells express a variety of activating receptors (NKRs), such as CD16, NKG2D, CD226 and NKp30, which might specifically recognize the ligands expressed on tumor cells. Based on the principle of NKR recognition, a strategy that targets NKRs is rapidly emerging. Given the promising clinical progress described in this review, CAR- and NKR-NK cell-based immunotherapy are likely promising new strategies for cancer therapy.

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…In comparison to the outstanding clinical results with CAR-engineered T cells, CAR-modified NK cells can reveal some advantages by additional cancer-killing mechanisms, especially antibody-dependent cell-mediated cytotoxicity (ADCC). In terms of safety conditions, unwanted adverse effects are avoided by short-term persistence and the lack of antigen clonality of CAR-modified NK cells [4-6]. CAR-redirected NK cells appear to have a beneficial impact and improved effects in immunosurveillance.…”

“…Currently, this leads to first immunotherapeutic approaches to cure both lymphomas of B cell origin and acute lymphoid leukaemia (ALL). This includes human NK cells of different origins, such as the NK cell line NK-92, primary cord blood (CB)-derived as well as peripheral blood (PB) NK cells, which have recently entered clinical implementation testing the effectiveness in different phase I/II studies (Table 1) [4, 8-10]. Other than primary NK cells collected from CB or PB, the transformed cell line NK-92 originated from undifferentiated NK-cell precursors [11-13].…”

“…Other than NK-92 cells, which can be expanded in cell culture, limiting amounts of primary NK cells challenged the development of NK cell-based therapeutic approaches. To solve this problem, a dose escalation phase I/II study with umbilical CB-derived CAR-engineered NK cells was authorised for patients with relapsed and refractory B-lymphoid malignancies (NCT03056339; Table 1) [4, 9]. In addition, the first clinical CAR-NK cell trials targeting antigens such as human epidermal growth factor receptor 2 (HER2), CD33, Mucin-1 (MUC1), CD7, and NK group 2, member D (NKG2D) ligands have been initiated (Table 1).…”

Challenges of NK cell-based immunotherapy in the new era

“…CAR-NK cells targeting well-known targets, such as CD19, CD20, SLAMP7, and EpCAM, have been tested in vivo with in-mouse models or in vitro. However, only few of these targets have proceeded to clinical trials, including CD19-CAR-NK cells and CD33-CAR-NK cells (NCT0194479, NCT00995137), and the results have not yet been reported [35]. Appropriate design of the CAR structure and transfection of the expression vectors into NK cells are challenging steps in the development of CAR-NK cells.…”

NK cell therapy after hematopoietic stem cell transplantation: can we improve anti-tumor effect?

“…The NK cell-mediated anti-tumor response could potentially be enhanced by transducing NK cells with a chimeric antigen receptor (CAR-NK), which recognizes tumor-specific antigens [46,47]. The CAR is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain.…”