Chimeric Antigen Receptor-Engineered Natural Killer (CAR NK) Cells in Cancer Treatment; Recent Advances and Future Prospects

Abstract

Graphical abstract Natural Killer (NK) cells are critical members of the innate immunity lymphocytes and have a critical role in host defense against malignant cells. Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) redirects the specificity of the immune cell against a target-specific antigen. ACT has recently created an outstanding opportunity for cancer treatment. Unlike CAR-armored T cells which hadnsome shortcomings as the CAR-receiving construct, Major histocompatibility complex (MHC)-independency, shorter lifespan, the potential to produce an off-the-shelf immune product, and potent anti-tumor properties of the NK cells has introduced NK cells as a potent alternative target for expression of CAR. Here, we aim to provide an updated overview on the current improvements in CAR NK design and immunobiology and describe the potential of CAR-modified NK cells as an alternative “off-the-shelf” carrier of CAR. We also provide lists for the sources of NK cells in the process of CAR NK cell production, different methods for transduction of the CAR genetic sequence to NK cells, the differences between CAR T and CAR NK, and CAR NK-targeted tumor antigens in current studies. Additionally, we provide data on recently published preclinical and clinical studies of CAR NK therapy and a list of finished and ongoing clinical trials. For achieving CAR NK products with higher efficacy and safety, we discuss current challenges in transduction and expansion of CAR NK cells, CAR NK therapy side effects, and challenges that limit the optimal efficacy of CAR NK cells and recommend possible solutions to enhance the persistence, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.

Development of Stem Cell-Derived Immune Cells for Off-the-Shelf Cancer Immunotherapies

“…NK cells are innate immune cells showing strong cytotoxicity against physiologically stressed cells such as tumor cells and virus-infected cells through multiple mechanisms of action. Their recognition of the target cell is independent of MHC expression [ 140 ]. NK cell activation and effector functions rely on the signals derived from both activating and inhibitory receptors.…”

“…NK cell activation and effector functions rely on the signals derived from both activating and inhibitory receptors. Activating signals include cytokine-binding receptors, integrins, killing-receptors (e.g., CD16, NKp30, NKp40, and NKp44) [ 140 ]. Inhibitory signals mainly come from receptors recognizing MHC-I, as well as some MHC-I non-related receptors [ 141 ].…”

“…Currently, Fate Therapeutics Company is conducting clinical trials based on the iPSC-derived NK products [ 146 ]. For example, FT596 is an investigational, universal, off-the-shelf iPSC-derived NK cell product engineered with hnCD16 and CD19 CAR (denoted as CAR.19-NKG2D-2B4-CD3ζ-IL15RF-hnCD16) [ 140 ]. The clinical trial is studying the efficacy of FT596 monotherapy and a combination of FT596 with a CD20 monoclonal antibody in the treatment of chronic lymphocytic leukemia and B cell lymphoma.…”

“…The clinical trial is studying the efficacy of FT596 monotherapy and a combination of FT596 with a CD20 monoclonal antibody in the treatment of chronic lymphocytic leukemia and B cell lymphoma. The Phase I interim result showed the treatments were well-tolerated, with no dose-limiting toxicities, and 10 out of 14 patients achieved the objected response [ 140 ].…”

DNAM-1-chimeric receptor-engineered NK cells, combined with Nutlin-3a, more effectively fight neuroblastoma cells in vitro: a proof-of-concept study

“…However, if advanced results have been obtained for hematopoietic tumors, in the context of solid tumors many efforts are still needed. Furthermore, adoptive transfer of extra vivo expanded and activated NK cells in autologous and allogeneic settings, in combination with monoclonal antibodies (mAbs) recognizing immune checkpoint molecules ( 30 , 31 ), activating cytokines and immunomodulatory drugs ( 25 , 32 ) or engineered for Chimeric Antigen Receptors (CARs) ( 33 ), emerges as one of the first-line anti-cancer cell immunotherapy strategies with an increasing number of therapeutic clinical successes [( 34 – 36 ), ClinicalTrial.gov and Supplementary Table S1 ].…”