Natural Killer Cell Immunotherapy: From Bench to Bedside

Abstract

The potential of natural killer (NK) cells to target numerous malignancies in vitro has been well documented; however, only limited success has been seen in the clinic. Although NK cells prove non-toxic and safe regardless of the cell numbers injected, there is often little persistence and expansion observed in a patient, which is vital for mounting an effective cellular response. NK cells can be isolated directly from peripheral blood, umbilical cord blood, or bone marrow, expanded in vitro using cytokines or differentiated in vitro from hematopoietic stem cells. Drugs that support NK cell function such as lenalidomide and bortezomib have also been studied in the clinic, however, the optimum combination, which can vary among different malignancies, is yet to be identified. NK cell proliferation, persistence, and function can further be improved by various activation techniques such as priming and cytokine addition though whether stimulation pre- or post-injection is more favorable is another obstacle to be tackled. Here, we review the various methods of obtaining and activating NK cells for use in the clinic while considering the ideal product and drug complement for the most successful cellular therapy.

Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy

“…131 Recent clinical studies have proven the usefulness of NK cell therapy for various cancer patients. 132, 133 For example, high-dose infusion (2 × 10 8 cells per kg) of ex vivo cultured NK cells following haploidentical hematopoietic cell transplantation significantly reduced leukemia progression (74–46%). 134 However, the success is still limited, and thus there is an urgent need to improve cancer immunotherapy using NK cells.…”

Preservation of cell-based immunotherapies for clinical trials

“…Allogeneic haploidentical NK cells have shown efficacy on tumors without inducing rejection or severe side effects in patients [55]. NK cells can also be derived from embryonic or induced pluripotent stem cells [56]. Robust allogeneic cell lines such as NK-92 have been used to develop cellular therapy products and can be more reliable than primary NK cells to achieve consistent product and large-scale production, although efficacy remains to be determined [54,57].…”

Short Term Hypoxia Synergizes with Interleukin 15 Priming in Driving Glycolytic Gene Transcription and Supports Human Natural Killer Cell Activities

“…Recently, NK cell treatment with IL-15, in addition to stimulation by cytokines (IL-2, -12, and -18) and binding of ligands for activating NK receptors, was shown to support switching to glycolytic metabolism, which involves nutrient-sensing mechanistic target of rapamycin (mTor) signaling and is a requirement for production of Ifn-␥ and cytolytic effector molecules (17)(18)(19)(20). Different signaling pathways thus underlie the effectiveness of IL-15 treatment and, consequently, of current ex vivo expansion and stimulation strategies that make use of this cytokine in NK cell-based immunotherapy of cancer (21)(22)(23)(24).…”

“…The future investigation of central carbon metabolism under hypoxia is warranted to better understand how cellular anabolism is balanced at low oxygen and regulates NK cell priming and further activation. This may lead to strategies for preparing NK cells for adoptive transfer therapy of cancer that overcome current limitations posed by poor tumor homing and by tumor immune evasion (23,24). …”