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Natural Killer Cells as Allogeneic Effectors in Adoptive Cancer Immunotherapy.

ABSTRACT: Natural killer (NK) cells are attractive within adoptive transfer settings in cancer immunotherapy due to their potential for allogeneic use; their alloreactivity is enhanced under conditions of killer immunoglobulin-like receptor (KIR) mismatch with human leukocyte antigen (HLA) ligands on cancer cells. In addition to this, NK cells are platforms for genetic modification, and proliferate in vivo for a shorter time relative to T cells, limiting off-target activation. Current clinical studies have demonstrated the safety and efficacy of allogeneic NK cell adoptive transfer therapies as a means for treatment of hematologic malignancies and, to a lesser extent, solid tumors. However, challenges associated with sourcing allogeneic NK cells have given rise to controversy over the contribution of NK cells to graft-versus-host disease (GvHD). Specifically, blood-derived NK cell infusions contain contaminating T cells, whose activation with NK-stimulating cytokines has been known to lead to heightened release of proinflammatory cytokines and trigger the onset of GvHD in vivo. NK cells sourced from cell lines and stem cells lack contaminating T cells, but can also lack many phenotypic characteristics of mature NK cells. Here, we discuss the available published evidence for the varying roles of NK cells in GvHD and, more broadly, their use in allogeneic adoptive transfer settings to treat various cancers.

SUBMITTER: Lupo KB

PROVIDER: S-EPMC6628161 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Natural Killer Cells as Allogeneic Effectors in Adoptive Cancer Immunotherapy.

Lupo Kyle B KB Matosevic Sandro S

Cancers 20190603 6

Natural killer (NK) cells are attractive within adoptive transfer settings in cancer immunotherapy due to their potential for allogeneic use; their alloreactivity is enhanced under conditions of killer immunoglobulin-like receptor (KIR) mismatch with human leukocyte antigen (HLA) ligands on cancer cells. In addition to this, NK cells are platforms for genetic modification, and proliferate in vivo for a shorter time relative to T cells, limiting off-target activation. Current clinical studies hav ...[more]

PMID: 31163679

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Project description: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.

Dataset Information

Natural Killer Cells as Allogeneic Effectors in Adoptive Cancer Immunotherapy.

Publications

Natural Killer Cells as Allogeneic Effectors in Adoptive Cancer Immunotherapy.

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