Multiple natural killer (NK) cell-based immune combination therapies are now under investigation as a strategy to further improve upon anti-tumor efficacy. NK cell immunotherapy has remained highly promising for over 30 years. Recently, advancements in NK cell biology have led to an understanding of the function of NK cells as a tool for effective cancer immunotherapy, and NK cell therapy is the subject of multiple Phase I/II clinical trials.
Chinese researchers recently reviewed advancements in NK cell immune therapy, with an emphasis on the biology of NK cells, the function and types of NK cell therapy, and clinical trials, as well as future perspectives on NK cell therapy, in the Journal of Translational Medicine (2022; https://doi.org/10.1186/s12967-022-03437-0). Many strategies have been developed for exploiting the anti-tumor properties of NK cells. NK cells characterize a specialized population of immune effector cells with a rapid response and powerful anti-tumor capacity, stated the researchers, led by Junfeng Chu, in the Department of Medical Oncology at The Affiliated Cancer Hospital of Zhengzhou University in China.
"In the past decade, clinical research on hematological cancers has pioneered the concept of peripatetic NK cell immunotherapy. Evidence suggests that NK cells have high safety and efficacy. Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer," the researchers stated.
In addition, antibodies that directly target NK cell inhibitory receptors can enhance NK cell responses and kill tumor cells. Some of these antibodies are currently being validated in clinical trials.
Activity of NK Cells
Innate immune cells consist of NK cells, dendritic cells, monocytes, and macrophages. Adaptive immune response cells, such as lymphocytes, interact with tumor cells through chemokines, adipose cytokines, and cytokines. NK cells, first identified and discovered in 1975, are a unique lymphocyte subpopulation, larger than T lymphocytes and B lymphocytes, the researchers stated.
NK cells are extensively distributed throughout lymphoid and as nonlymphoid tissues, consisting of the bone marrow, liver, lungs, lymph nodes, spleen, liver, and peripheral blood. They recognize their targets through the identification of numbers of stimulating as well as suppressive signals, whose outcomes depend on the nature of the target cells. Several regulatory cytokines induce the functions of NK cells as tumor targets, and numerous cytokines that activate NK cells are presently undergoing clinical or preclinical development, they stated.
Because NK cells are stimulated through the initial recognition of certain "stress" or "danger" signals, tumor cells are ideal NK cell targets, the researchers stated. Direct cytotoxicity mediated by NK cells exerts significant anticancer effects. NK cells can also have indirect cancer-killing effects by promoting anti-tumor activity. Many clinical approaches have been applied to kill cancer cells through NK cell stimulation, including cytokines, autologous as well as allogeneic NK cells, and gene-edited chimeric antigen receptor (CAR)-NK cell immune therapy.
Both allogeneic and autologous NK cell therapy have demonstrated clinical efficacy, either alone or in combination with conventional therapies. Some 50 clinical trials are presently underway, including in acute myeloid leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, multiple myeloma, non-Hodgkin lymphoma, neuroblastoma, renal cell carcinoma, melanoma, ovarian cancer, and breast cancer.
CAR-NK Cells
The success of CAR T-cell therapy targeting CD19 in the design of genetically modified cell treatments for cancer also stimulated interest in the preparation of CAR-NK cells for tumor immune therapy. The researchers stated that "the expansion the function of CAR-modified NK cells within the existing approach to cancer immunotherapy is promising." CAR-NK cell therapy has yielded preclinical anti-malignant activity both in hematological cancers and solid tumors, including leukemia, lymphoma, myeloma, ovarian cancer, and glioblastoma, and the therapy has exhibited some efficacy.
NK cells have some powerful therapeutic advantages over CAR T-cell therapy, the researchers stated: they are more widely available, can be derived from allogeneic cells, and do not need to rely on the patient's own specific immune cells; they do not require major histocompatibility complex molecules for antigen presentation or antigen activation and can target a wide range of pathogenic antigens with greater cytotoxicity; they do not secrete the major cytokines that trigger cytokine release syndrome and can greatly mitigate the risk of adverse effects; and allogeneic NK cells also do not cause graft-versus-host reactions.
NK cell therapy does have some difficulties and dilemmas. The first hurdle for CAR-NK cell immunotherapy is in vitro expansion of NK cells. The number of NK cells from a single donor is not sufficient for therapy, which makes the expansion and activation of NK cells critical. This production process usually takes 2-3 weeks to culture NK cells. Therefore, obtaining enough NK cells remains a challenge, the researchers stated. Selecting the appropriate method for transducing CARs into NK cells is also key to CAR-NK cell immunotherapy.
Mark L. Fuerst is a contributing writer.