Table 2.
Preclinical approaches with CAR-NK cell therapeutics for brain tumors.
| Target | Cell type | Malignancy | Treatment | Outcome | Ref |
|---|---|---|---|---|---|
| ErbB2 (HER2) | NK-92 | Breast cancer brain metastases | Orthotopic xenografts in athymic nude rats. Administered by I.V. injection. | Early intensive treatment with targeted NK-92 cells and ultrasound improved survival compared with biweekly treatments or either treatment alone. The intensive treatment paradigm resulted in long-term survival in 50% of subjects. | 210 |
| EGFR | NK-92, PB-NK | Breast cancer brain metastases | Orthotopic xenografts in NSG mice. Administered by intratumoral injection. | EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. Intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. | 106 |
| GD2 | NK-92 | Neuroblastoma | In vitro only. | Enhanced cell killing was strictly dependent on specific recognition of the target antigen and could be blocked by GD2-specific antibody or anti-idiotypic antibody occupying the CAR’s cell recognition domain. | 211 |
| EGFR and EGFRvIII | NK-92 | Glioblastoma | Orthotopic xenografts in NSG mice. Administered by intratumoral injection. | In vitro analysis revealed high and specific cytotoxicity of EGFR-targeted NK-92 against established and primary human GBM cells, which was dependent on EGFR expression and CAR signaling. In immunodeficient mice carrying intracranial GBM xenografts local treatment with dual-specific NK cells was superior to treatment with the corresponding monospecific CAR NK cells. This resulted in a marked extension of survival. | 104 |
| EGFR and EGFRvIII | NKL | Glioblastoma | Orthotopic xenografts in NSG mice. Administered by intratumoral injection. | EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with glioblastoma cells or patient-derived glioblastoma stem cells in an EGFR-dependent manner. Intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. | 85 |
| GD2 | NK-92-MI | Neuroblastoma | Orthotopic xenografts in NSG mice. Administered by intratumoral injection. | CAR NK-92 cells induced specific killing of GD2-expressing cells in vitro and in vivo, associated with enhanced production of interferon-γ. | 91 |
| EGFRvIII | YTS | Glioblastoma | Subcutanous xenografts in NMRI nude mice. Administered by intravenous injection. | EGFRvIII-CAR confers specific cytotoxicity of NK cell towards EGFRvIII+ glioblastoma cells in vitro and to established subcutaneous U87-MGEGFRvIII tumor xenografts. | 212 |
| EGFRvIII | KHYG-1 | Glioblastoma | In vitro only. | EGFR-CAR-KHYG-1 inhibited GBM cell-growth via apoptosis in an EGFRvIII-expressing specific manner. | 213 |
| EGFRvIII | KHYG-1 | Glioblastoma | Subcutaneous xenografts in NOD/SCID mice. Administered by subcutaneous injection. | EGFR-CAR-KHYG-1 cells led to expression of cellular immunity-related cytokines on EGFRvIII-expressing U87MG in vitro but did not inhibit tumor progression in vivo. | 214 |
| GD2 | NK-92 | Neuroblastoma | Subcutaneous xenografts in NSG mice. Administered by peritumoral injection. | NK-92-scFv(ch14.18)-zeta to effectively lyse GD2( + ) neuroblastoma cells also including partially or multidrug-resistant lines. NK-92-scFv(ch14.18)-zeta is able to mediate a significant anti-tumor response in vivo in a drug-resistant GD2( + ) neuroblastoma xenograft mouse model. | 215 |
| ErbB2 (HER2) | NK-92 | Glioblastoma | Orthotopic xenografts in NSG mice. Administered by intratumoral injection. | Potent in vivo anti-tumor activity of NK-92/5.28.z (GD2) was observed in orthotopic GBM xenograft models in NSG mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area. Local therapy with NK-92/5.28.z cells resulted in cures of transplanted syngeneic GBM in four of five mice carrying subcutaneous tumors and five of eight mice carrying intracranial tumors. | 105 |
| GD2 | PB-NK | Neuroblastoma | In vitro only. | Genetic modification with 14.G2a-2B4ζ significantly enhanced the activation response of NK cells to the neuroblastoma cell line JF. JF cells were susceptible to lysis by two of three unmodified NK cell cultures, but resistance to the third NK cell line was successfully overcome by the signal-enhanced receptor. | 216 |