Retargeting NK‐92 for anti‐melanoma activity by a TCR‐like single‐domain antibody

Abstract

The efficacy of immunotherapy based on natural killer (NK) cells is hampered by intrinsic non-specific cytotoxicity and insufficient activation of NK cells. Here, we confer the T-cell receptor-like (TCR-like) specificity on NK cells, taking advantage of both the innate and adaptive immune arms of the immune response to generate enhanced anti-melanoma activity. The TCR-like antibody (Ab) GPA7 was selected against melanoma-associated gp100/human leukocyte antigen (HLA)-A2 complex and then fused to intracellular domain of CD3-ζ chain. This fusion construct was incorporated into NK-92MI cell line and expressed as a chimeric antigen receptor on the surface of the cell. The anti-tumour activity of the transgenic NK-92MI-GPA7-ζ cell line was assessed against melanoma in vitro and in vivo. The engineered NK-92MI-GPA7-ζ cells could recognize melanoma cells in the context of HLA-A2 and showed enhanced killing of both melanoma cell lines and primary melanoma. Furthermore, adoptively transferred NK-92MI-GPA7-ζ cells significantly suppressed the growth of human melanoma in a xenograft model in mice. Collectively, these results demonstrate that the TCR-like Ab, GPA7, could redirect NK cells to target the intracellular antigen gp100 and enhance anti-melanoma activity, providing a promising immunotherapeutic strategy to prevent and treat melanoma.

Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy

“…The PDX model, which is established by transferring of primary tumors directly from the patient into an immunodeficient mouse, can retain the heterogeneity of primary tumor samples and more closely resembles the original clinical cancer than long-established cell lines and standard xenografts; thus, this model has emerged as a powerful tool for studying tumor xenografts [32] . Most CAR-NK cells are transferred to the PDX model to evaluate their safety and efficacy in pre-clinical trials, including CAR-targeting antigens from hematological cancers (eg, CD19, CD20, CD138, and CS-1) [33][34][35][36][37][38] and solid tumors (eg, HER2, EpCam, GD2, GPA7, PSCA, EGFR and EGFRvIII) [14,26,[39][40][41][42][43][44][45][46] (Table 1).…”

The Rise of Allogeneic Natural Killer Cells As a Platform for Cancer Immunotherapy: Recent Innovations and Future Developments

“…NantKwest, is actively involved in enhancing the functions of its lead product, parental NK-92 cells (activated NK cells, aNK), through gene modifications employing CARs to make them target specific. NK-92 CARs (taNK) are developed against tumor markers in NB (GD2), melanoma (GPA7) (91), breast cancer (EpCAM, HER-2, EGFR) (92, 93), MM [CS1 (94), CD138 (95)], and leukemias (CD19, CD20) (96) and have shown efficacy in preclinical studies. In an alternative approach, NK-92 cells have also been modified to express CD16a (high affinity NK cells, haNK) to promote ADCC (97).…”

NK cells and cancer: you can teach innate cells new tricks

“…142) and CD20 (REF. 143) expressed on B cell malignancies; disialoganglioside G D2 , a glycolipid expressed on neuroblastoma 144 and various other cancer types 145 ; HER2 (also known as ERBB2), an antigen expressed by tumours of epithelial origin [146][147][148] ; epithelial cell adhesion molecule (EPCAM), a molecule over expressed by carcinomas and cancer stem cells 149 ; HLA-A2 loaded with the mela noma antigen gp100 (also known as PMEL) 150 ; prostate stem cell antigen (PSCA) 151 ; and CD138 (also known as SYND1), which is expressed by multiple myeloma cells 152 . Because NK-92 cells are a tumour cell line infected with Epstein-Barr virus (EBV), they must be irradiated to prevent their proliferation before being adoptively transferred.…”