Overcoming Resistance to Natural Killer Cell Based Immunotherapies for Solid Tumors

Abstract

Despite advances in the diagnostic and therapeutic modalities, the prognosis of several solid tumor malignancies remains poor. Different factors associated with solid tumors including a varied genetic signature, complex molecular signaling pathways, defective cross talk between the tumor cells and immune cells, hypoxic and immunosuppressive effects of tumor microenvironment result in a treatment resistant and metastatic phenotype. Over the past several years, immunotherapy has emerged as an attractive therapeutic option against multiple malignancies. The unique ability of natural killer (NK) cells to target cancer cells without antigen specificity makes them an ideal candidate for use against solid tumors. However, the outcomes of adoptive NK cell infusions into patients with solid tumors have been disappointing. Extensive studies have been done to investigate different strategies to improve the NK cell function, trafficking and tumor targeting. Use of cytokines and cytokine analogs has been well described and utilized to enhance the proliferation, stimulation and persistence of NK cells. Other techniques like blocking the human leukocyte antigen-killer cell receptors (KIR) interactions with anti-KIR monoclonal antibodies, preventing CD16 receptor shedding, increasing the expression of activating NK cell receptors like NKG2D, and use of immunocytokines and immune checkpoint inhibitors can enhance NK cell mediated cytotoxicity. Using genetically modified NK cells with chimeric antigen receptors and bispecific and trispecific NK cell engagers, NK cells can be effectively redirected to the tumor cells improving their cytotoxic potential. In this review, we have described these strategies and highlighted the need to further optimize these strategies to improve the clinical outcome of NK cell based immunotherapy against solid tumors.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…These include concerns regarding potential autoimmune cytotoxicity for therapies such as cytokine administration and immune checkpoint inhibitors, the magnitude of the patient response to treatment, and patient relapse due to innate or acquired resistance (15)(16)(17)(18). Moreover, though some NK cell based treatments have shown promising results for hematological malignancies, NK cells generally have low capacity to infiltrate solid tumors, and so far, the efficacy against advanced cancers and solid tumors remains relatively low (19). Cytolytic immune cells such as NK cells and CD8 + T-cells are also suppressed through multiple pathways in the tumor microenvironment (TME) (20,21).…”

Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNK

“…haNK cells had a surface expression of 60%. We hypothesized that ADCC mediated by the anti-PD-L1 IgG 1 avelumab would ameliorate potential suppression (30). Avelumab or healthy donor NK cells as single agents induced minimal meningioma cell lysis, as measured by indium release from tumor cells.…”

Targeting Natural Killer Cells for Tumor Immunotherapy

“…A combination comprising an ADAM metallopeptidase domain 17 inhibitor further enhanced the function of NK cells by preventing CD16 shedding from the membrane of NK cells (102). Multiple other CD16-directed BiKEs, such as CD16 × Erb-B2 receptor tyrosine kinase 2, CD16 × human epidermal growth factor receptor 2/neu, CD16 × EGFR, CD16 × carcinoembryonic antigen, and CD16 × EpCAM, are under investigation (103). A bi-specific Ab-recognizing CS1-NKG2D, which comprises an anti-NKG2D scFv and an anti-CS1 scFv, showed enhanced cytotoxicity and cytokine production from NK cells and significantly prolonged their survival in a multiple myeloma xenograft NOD-SCID IL2γc−/− (NSG) mouse model (104).…”

“…One of the most important immunosuppressive cytokine is TGF-β, which is secreted by tumor cells, Tregs, MDSCs, and other stromal cells in the TME to hamper the antitumor immune response. NK cell antitumor function is inhibited by TGF-βmediated downregulation of the expression of NK-activating receptors NKp30 and NKG2D and also reduces the expression of NKG2D ligands on tumor cells, thus suppressing NKmediated cytotoxic capacity and IFN-γ secretion (103). TGF-β also affects the development and differentiation of human NK cell subsets (128).…”