Challenges to the broad application of allogeneic natural killer cell immunotherapy of cancer

Abstract

Natural killer (NK) cells are innate immune cells that recognize malignant cells through a wide array of germline-encoded receptors. Triggering of activating receptors results in cytotoxicity and broad immune system activation. The former is achieved through release of cytotoxic granules and presentation of death receptor ligands, while the latter is mediated by inflammatory cytokines, such as interferon-γ and tumor necrosis factor α. Early success with ex vivo activation of NK cells and adoptive transfer suggest they are a safe therapeutic with promising responses in advanced hematologic malignancies. In particular, adoptive NK cell therapies can serve as a ‘bridge’ to potentially curative allogeneic stem cell transplantation. In addition, strategies are being developed that expand large numbers of cells from limited starting material and mature NK cells from precursors. Together, these make ‘off-the-shelf’ NK cells possible to treat a wide range of cancers. Research efforts have focused on creating a range of tools that increase targeting of therapeutic NK cells toward cancer—from therapeutic antibodies that drive antibody-dependent cellular cytotoxicity, to chimeric antigen receptors. As these novel therapies start to show promise in clinical trials, the field is rapidly moving toward addressing other challenges that limit NK cell therapeutics and the goal to treat solid tumors. This review describes the state of therapeutic NK cell targeting of tumors; discusses the challenges that need to be addressed before NK cells can be applied as a wide-ranging treatment for cancer; and points to some of the innovations that are being developed to surmount these challenges. Suppressive cells in the tumor microenvironment pose a direct threat to therapeutic NK cells, through presentation of inhibitory ligands and secretion of suppressive cytokines and metabolites. The nutrient- and oxygen-starved conditions under which NK cells must function necessitate an understanding of therapeutic NK cell metabolism that is still emerging. Prior to these challenges, NK cells must find their way into and persist in the tumor itself. Finally, the desirability of a ‘single-shot’ NK cell treatment and the problems and benefits of a short-lived rejection-prone NK cellular product are discussed.

A tri-specific killer engager against mesothelin targets NK cells towards lung cancer

“…We would predict, therefore, that the IL-15 component of this TriKE, which targets lung cancer, would also enhance infiltration of NK cells directly into the tumor, but this remains to be shown. Once within the tumor microenvironment, many challenges remain to NK cell function, such as hypoxia (58), which were not investigated here.…”

TCR-NK Cells: A Novel Source for Adoptive Immunotherapy of Cancer

“…Recent clinical experience with CAR-modified allogeneic NK cells has shown that they can expand and persist at low levels in vivo for at least 12 months [ 71 ]. Further research into the combination of NK cell infusions with immune checkpoint inhibitors is expected to further the likelihood of the long-term persistence and elevated activity of adoptively transferred NK cells [ 89 ].…”

The prevention of disease relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia

“…The rationale behind NK-DLI is the strong alloreactivity exerted by NK cells respect to tumor antigens, without inducing high rates of potentially fatal GvHD. The problem with such a therapeutic modality lies in the shortpersistence of NK cells, mainly due to the inhibition played by regulatory T-cells (Treg) and myeloid suppressor cells on one side, and by tumor-induced NK cells anergy on the other (63)(64)(65). Several strategies have focused on generating large number of NK cells persisting in vivo, to retain their efficacy in the longterm.…”