Chimeric antigen receptor-based natural killer cell immunotherapy in cancer: from bench to bedside

Abstract

Immunotherapy has rapidly evolved in the past decades in the battle against cancer. Chimeric antigen receptor (CAR)-engineered T cells have demonstrated significant success in certain hematologic malignancies, although they still face certain limitations, including high costs and toxic effects. Natural killer cells (NK cells), as a vital component of the immune system, serve as the “first responders” in the context of cancer development. In this literature review, we provide an updated understanding of NK cell development, functions, and their applications in disease therapy. Furthermore, we explore the rationale for utilizing engineered NK cell therapies, such as CAR-NK cells, and discuss the differences between CAR-T and CAR-NK cells. We also provide insights into the key elements and strategies involved in CAR design for engineered NK cells. In addition, we highlight the challenges currently encountered and discuss the future directions in NK cell research and utilization, including pre-clinical investigations and ongoing clinical trials. Based on the outstanding antitumor potential of NK cells, it is highly likely that they will lead to groundbreaking advancements in cancer treatment in the future.

Emerging roles of CAR-NK cell therapies in tumor immunotherapy: current status and future directions

“…These protocols often involve the use of cytokines such as IL-15 or a combination of IL-15, IL-21 and stem cell factor (SCF) to promote cell growth while maintaining cytotoxic capabilities [ 46 ]. Advances in gene editing technologies have also enabled more efficient insertion of CAR constructs into UCB-derived NK cells, enhancing their specificity and killing capacity against target cancer cells [ 47 – 51 ]. Despite the challenges, the ongoing optimization of techniques for the cultivation and genetic modification of UCB-derived NK cells continues to solidify their role as a valuable resource in the development of innovative immunotherapies.…”

Harnessing natural killer cells for refractory/relapsed non-Hodgkin lymphoma: biological roles, clinical trials, and future prospective

“…NK cells, a specialized subset of innate lymphoid cells (ILCs), can distinguish between self-cells and non-self-cells through the recognition of self-major histocompatibility complex (MHC) I molecules [ 12 , 13 ]. They constitute approximately 10–15% of the lymphocyte population in peripheral blood, and characterized as large granular lymphocytes with kidney-shaped nuclei, a high cytoplasm-to-nucleus ratio, and large azurophilic granules in cytoplasm [ 14 , 15 ].…”

“…They constitute approximately 10–15% of the lymphocyte population in peripheral blood, and characterized as large granular lymphocytes with kidney-shaped nuclei, a high cytoplasm-to-nucleus ratio, and large azurophilic granules in cytoplasm [ 14 , 15 ]. NK cell development and maturation primarily occur in the bone marrow, where common lymphoid progenitors (CLPs) differentiate into NK precursors (NKPs), immature NK cells, and finally mature NK cells [ 12 ]. Notably, recombinant interleukin (rIL)-15 plays a crucial role in NK cell development from hematopoietic stem cells [ 16 ].…”