NK Cell-Mediated Eradication of Ovarian Cancer Cells with a Novel Chimeric Antigen Receptor Directed against CD44

Abstract

Ovarian cancer is the most common cause of gynecological cancer-related death in the developed world. Disease recurrence and chemoresistance are major causes of poor survival rates in ovarian cancer patients. Ovarian cancer stem cells (CSCs) were shown to represent a source of tumor recurrence owing to the high resistance to chemotherapy and enhanced tumorigenicity. Chimeric antigen receptor (CAR)-based adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. In this study, we developed a codon-optimized third-generation CAR to specifically target CD44, a marker widely expressed on ovarian cancer cells and associated with CSC-like properties and intraperitoneal tumor spread. We equipped NK-92 cells with the anti-CD44 CAR (CD44NK) and an anti-CD19 control CAR (CD19NK) using lentiviral SIN vectors. Compared to CD19NK and untransduced NK-92 cells, CD44NK showed potent and specific cytotoxic activity against CD44-positive ovarian cancer cell lines (SKOV3 and OVCAR3) and primary ovarian cancer cells harvested from ascites. In contrast, CD44NK had less cytotoxic activity against CD44-negative A2780 cells. Specific activation of engineered NK cells was also demonstrated by interferon-γ (IFNγ) secretion assays. Furthermore, CD44NK cells still demonstrated cytotoxic activity under cisplatin treatment. Most importantly, the simultaneous treatment with CD44NK and cisplatin showed higher anti-tumor activity than sequential treatment.

Enzyme-triggered- and tumor-targeted delivery with tunable, methacrylated poly(ethylene glycols) and hyaluronic acid hybrid nanogels

“…The flow cytometry results for 24-hour incubation of DOX-loaded NGs at levels of DOX below of the typical noticed cytotoxicity (lower that IC50 values; see Figure 11 ) exhibited significantly higher, from 40% to 70%, entry of DOX-loaded NGS to both types of cancer cell lines (MCF-7, A2780) compared to free drug, respectively. It should be noticed that much lower level was noticed for A2780 cell lines that not possess overexpressed typical cellular receptors (CD44, RHAMM) that are characteristic for the interaction of HA (Klapdor et al., 2021 ). The increased level of NGs that entered the MCF-7 suggested that targeted behavior of proposed NGs was enhanced.…”

CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances

“…Importantly, it was demonstrated that sequential combination therapy with cisplatin followed by CD133-CAR-NK and CD44-CAR-NK92 cells led to the strongest killing effect on ovarian cancer stem cell lines compared to control NK cells [ 252 , 253 ] (Fig. 3 A).…”

Application of natural killer immunotherapy in blood cancers and solid tumors

“…For example, prostate stem cell antigen-directed CAR NK cells have shown promising therapeutic efficacy for pancreatic cancer in a preclinical study [11]. Engineered CAR-NK cells targeting CD44, a marker abundantly expressed by ovarian cancer cells, showed potent cytotoxicity against CD44-positive ovarian cancer cells [20]. In lung adenocarcinoma, CAR-NK92 cells targeting mesenchymal-epithelial transition factor (C-Met) showed promising results in lung xenograft models [21].…”