Table 1.
Summary of current academic investigations and clinical trials into NK cell immunotherapy directed against malignant tumors of the CNS.
| Therapeutic Strategy | Treatment | Results summary | Model (tumor type) | Reference/Trial ID |
|---|---|---|---|---|
| Combinational therapy NK cells and chemotherapy | NK cells infusion with: Sulindac; MAPK and cyclin-dependent kinase 4/6 inhibitors (38) |
Reduces VEGF secretion and increases NK cell cytotoxicity; Suppresses tumor proliferation and increases NK cell cytotoxicity | Human (GBM, Lung cancer) | (37, 38) |
| Sensitization of tumors to NK cell cytotoxicity | NK cell infusion with BTZ |
Predisposes tumor to NK natural cytotoxicity and TRAIL/DR5; BTZ and NK cell infusion increased tumor elimination | Mouse (BG7); mouse (U87) | (39, 40) |
| Virotherapy | Triple therapy (NK cell infusion, BTZ, oHSV) | Tumor clearance tumor bearing mice; combinational therapy with BTZ and oHSV enhances tumor death and NK cell activation | Mouse (GBM30) | (41, 42) |
| TGF-β and oHSV infection | Modulated NK cell immune response to oHSV infected cells and improved anti-GBM effect of the oHSV treatment | Mouse (GB30) | (43) | |
| Overcoming immunosuppressive TME | siRNA interference of TGF-β signaling; infusion of TGF-β receptor negative NK cells | Reduction of tumorigenic profile of glioma; NK cells were resistant to TGF-β inhibition | Mouse (LNT229); in vitro; in vitro | (44–46) |
| Toll-like receptor agonism | CpG-ODN DNA TLR-9 agonism | Clinical trials failed to recapitulate results of encouraging in vitro TLR-9 agonism | Clinical trial (GBM); mouse (GL621) | (47–50) |
| Poly-ICLC TLR-3 agonism with bevacizumab (a-VEGF) | Poly-ICLC adjuvant to tumor associated antigens mixed with Bevacizumab—study unfinished, promising in vitro results | Human trial (GBM) | NCT02754362 (withdrawn—personnel changes) | |
| Directing NK cell immunity toward brain tumor antigens | Infusion of monalizumab (a-NKG2A)/cetuximab (a-EGFR) | NKG2A blockage potential to boost ADCC against GBM. Cetuximab treatment increased ADCC mediated by CD16+ NK cells (IL-2 or lectin-activated) | Human GBM stem cells in vitro | (51) |
| Infusion of CAR NKs engineered to be specific for EGFR, EGFRVIII, Erbb2 | EGFR, EGFRvIII CAR NK cells suppressed tumor growth and significantly prolonged survival; CXCR4 transduction enhanced antitumor responses of EGFR CAR NK cells; Erbb CAR NK cells | Mouse (GB19 xg); mouse (U87 xg); mouse (GL621 xg) | (52–54) | |
| Infusion of a-NG2/CSPG4 Ab | NK cell directed ADCC and proinflammatory tumor environment enhancing survival | Rat (U87); mouse (GBM) | (55, 56) | |
| Immune checkpoint blockade | Infusion of a-PD-1 and a-CTLA-4 Ab | Interference with peripheral immune cell inhibition potentiates intracranial immune response; immune checkpoint blockade antibodies improved survival in models | Mouse(GL621); mouse (B16) | (57, 58) |
| Blockade of interactions of HLA-E:CD94/NKG2A or LLT1/CD161 with siRNA or blocking Ab | Blockade promoted NK cell lysis | Human (GBM) in vitro | (59, 60) | |
| Circumventing the BBB | Infusion of a-CTLA-4/a-PD-1 Ab conjugated to biopolymer scaffold | Treatment able to cross BBB. Prolonged survival of mice compared to free a-CTLA-4 and a-PD-1 Ab | Mouse (GL261) | (61) |
| Autologous NK cell infusion expanded ex vivo | Artificial antigen-presenting cells | Promising in vitro, results forthcoming | Human trial (Recurrent MBM) | NCT02271711 (active) |
| Cytokines/Feeder cells + infusion recombinant human interleukin-15 | Promising in vitro, results forthcoming | Human (Solid brain tumors, SCM, NBM) | NCT01875601 (complete) | |
| Cancer/testis antigens presented by DNA-demethylated TH cells | Labeled cells infiltrated tumor site (SPECT imaging). Reduced disease burden 5 out of 10 patients. Long term survival in 3 of 10. However, slow kinetics of induced antitumor response | Human trial (GBM) | NCT01588769 (complete) | |
| Genetically modified feeder-cells | Promising in vitro, results forthcoming | Human trial (GBM) | NCT04254419 (not yet recruiting) | |
| Allogeneic (HLA)-haploidentical hematopoietic cell transplantation | Allo HTC and infusion with donor NK cells | Promising in vitro, results forthcoming | Human trial (eSCM, rSCM, oSCM, NBM) | NCT02100891 (recruiting) |
Abbreviated cancers: GBM, glioblastoma; MBM, medulloblastoma; NBM, neuroblastoma; e, Ewing; SCM, sarcoma; r, Rhabdomyosarcoma; o, Osteosarcoma. Other abbreviations: xg, Xenograft; VEGF, vascular endothelial growth factor; BTZ, bortezomib; oHSV, oncolytic herpes simplex virus; TGF-β, transforming growth factor-beta; EGFR, epidermal growth factor receptor; Ab, antibody.