Are NK-Cell–Based Treatments the Next Approach in Immuno-Oncology?

Highlighting their ability to quickly destroy malignant cells without antigen specificity, natural killer (NK) cells have been identified as an opportunity for use, particularly in cases where T cells are not effective.

Amid efforts to improve and expand the use of chimeric antigen receptor (CAR) T-cell therapy, researchers of a new study are outlining the potential of CAR natural killer (NK)-cell–based treatment in oncology.

Highlighting their ability to quickly destroy malignant cells without antigen specificity, the authors identified the opportunities to use NK cells, particularly in cases where T cells are not effective.

“NK cells have been explored for adoptive immunotherapy in a number of different cancers, particularly in leukemia and lymphoma, given their recognized graft-versus-leukemia (GvL) effect,” commented the researchers. “The adoptive transfer of NK cells after ex vivo activation has been shown to be safe and well-tolerated in lymphomas, breast and lung cancer, and metastatic RCC patients. The adoptive transfer of non-modified or genetically engineered NK cells could provide a more innovative therapeutic approach for cancer immunotherapy.”

There are currently 23 trials evaluating genetically engineered NK cells, most of which are exploring the use of NK-92–derived CAR NK cells for use in hematological malignancies and solid tumors. The researchers noted that CD16 is not present in NK-92 cells, limiting its use with monoclonal antibodies that rely on ADCC function. Results from 2 trials of multiple myeloma and glioblastoma are anticipated.

CAR NK-cell­–based treatments offer several advantages over CAR T-cell therapies. While CAR T transfer is limited to autologous T cells to prevent the risk of GvHD, CAR NK cells can be transferred from both autologously and from allogeneic sources. CAR T-cell therapies require high manufacturing costs, uncertainty of collecting enough cells, and time for generation and expansion. CAR NK-cell therapy, explained the researchers, offers an “off-the-shelf” approach. Notably, CAR NK-cell therapy carries a low risk of cytokine release syndrome—a well-known adverse effect of CAR T-cell therapy.

NK cells have also been explored as adoptive transfer therapy, from both autologous and allogeneic sources. While autologous transfer is considered a safer choice due to their compatibility, there is a reduced antitumor effect due to lower CD107a degranulation, tumor necrosis factor–α, and interferon-γ production. While there have been attempts to improve antitumor effects by expanding NK cells for adoptive transfer in vivo, inefficient results have been seen in acute leukemias and in solid tumors as the reinfused NK cells remain in circulation have a limited tumor-homing ability.

“Due to the suboptimal efficacy of autologous NK cell infusions, allogeneic NK cells have been heavily assessed as a source for NK cell adoptive transfer therapy. Allogeneic NK cells can be obtained from peripheral blood, umbilical cord blood, pluripotent stem cells, and commercially available NK cell lines such as NK-92. They can provide an ‘off-the-shelf’ option that can reduce manufacturing costs and dose escalation protocols, and make reproducibility much easier.”

According to the researchers, allogeneic alloreactive NK cells offer a protective role against graft versus host disease (GVHD), similar to that seen with CAR NK-cell therapy. The reason for this protective ability, explained the group, is the ability of NK cells to work in a non–antigen specific way and their regulation of immune cells that are typically involved in the GVHD process.


Mendoze-Valderrey A, Alvarez M, De Maria A, Margolin K, Melero I, Ascierto M. Next generation immune-oncology strategies: unleashing NK cells activity. Cells. 2022;11(19):3147

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