Current strategies exploiting NK‐cell therapy to treat haematologic malignancies

Abstract

Natural killer (NK) cells recognize targets that have been changed via malignant transformation or infection. Previously, NK cells were thought to be short-lived, but we now know that NK cells can be long-lived and remember past exposures in response to CMV. NK cells use a plethora of activating and inhibitory receptors to recognize these changes and attack targets, but tumour cells often evade NK cells. Therefore, major efforts are being made to hone in on NK cell antitumour properties in immunotherapy. In the clinical setting, haploidentical NK cells can be adoptively transferred to help treat cancer. To expand NK cells in vivo and enhance tumour targeting, IL-15 is being tested in combination with a glycogen synthase kinase (GSK) 3 inhibitor (CHIR99021), an inhibitor that has been shown to expand mature, highly functional NK cells capable of killing multiple tumour targets. One major limitation to NK cell therapy is lack of specificity. To address this concern, bispecific or trispecific engagers that target NK cells to the tumour and an ADAM17 inhibitor that prevents CD16 shedding after NK cell activation are being tested. Additionally, monoclonal antibodies are being designed to redirect the inhibitory signals that limit NK cell functionality. Further understanding of the biology of NK cells will inform strategies to exploit NK cells for therapeutic purposes.

Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer

“…Although diverse forms of IL-15 monotherapy augment the number of NK and CD8 T cells, due to immunological checkpoints, IL-15 will have to be used in combination therapy if it is to become a major factor in the cancer therapy armamentarium (Evans et al, 1997;Romee et al, 2012;Ochoa et al, 2017aOchoa et al, , 2017bJohnson and Miller, 2018).…”

Gene Regulatory Programs Conferring Phenotypic Identities to Human NK Cells

“…Natural killer (NK) cells provide protection from viral infections or cancer via their cytolytic function and interferon gamma (IFNg) production. A major clinical goal is to harness these NK cell functions for tumor immunotherapy (Baggio et al, 2017;Johnson and Miller, 2018;Romee et al, 2016). In addition, NK cells have been implicated in the control of HIV infection either directly or by antibody-mediated lysis of infected cells (Bradley et al, 2018;Ramsuran et al, 2018).…”

Exploiting NK Cell Surveillance Pathways for Cancer Therapy

“…Thus, more basic research into the molecular basis and cell biology of activating NK cell receptor signalling in response to soluble tumour ligands, such as PDGF-DD and MULT1, is required and will inform methods to enhance NK cell targeting to tumours and stimulate their functions in vivo. For most cancers, only a subset of patients exhibit durable anti-tumour responses following immunotherapy and relapse remains a significant problem for haematological malignancies following HCST [54,119] and so strategies to exploit favourable donor immunogenetics are also warranted (e.g., KIR/HLA as well as CD16 genotypes). These latter strategies will have the added benefit of informing basic research into NK cell education and the generation of adaptive ‘memory’ NK populations.…”

“…The selective inhibition of CD16 cleavage by an ADAM17 inhibitor led to increased IFN-γ production [118]. Clinical studies are now being conducted using ADAM17 inhibitors in combination with anti-CD20 rituximab after HCST in patients with diffuse large B cell lymphoma [119].…”