Epithelial ovarian cancer (EOC) is a common and aggressive gynecologic malignancy that is often asymptomatic in its early stages. Most patients are diagnosed at an advanced stage, by which time the tumor may have already metastasized; floating growth in ascites and peritoneal implantation are its primary modes of spread. Although initial treatment for EOC often yields favorable results, the majority of patients eventually develop resistance to chemotherapy, leading to disease recurrence and even death. Mesothelin (MSLN) is a glycosylphosphatidylinositol-anchored cell surface glycoprotein that is overexpressed in various cancers, with the highest expression found in ovarian cancer. Its high expression is associated with advanced tumor staging and high metastatic rates, making it a critical target for diagnosis, prognostic uation, and the development of therapeutic strategies. Treatments targeting mesothelin are under active investigation and have shown promise for EOC.

With the rise of immunotherapy, particularly the remarkable success of Chimeric Antigen Receptor (CAR) T-cell therapy in hematologic malignancies, scientists have begun exploring its potential in solid tumors, especially EOC. In innovative EOC research, investigators at the Dana-Farber Cancer Institute discovered that their engineered cytokine-induced memory-like NK cells (CIML NK) not only demonstrated superior anti-tumor activity in vitro but also significantly inhibited tumor growth and metastasis in in vivo models. This research was published in the journal Science Advances under the title "CAR memory–like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer." Currently, Shenzhen Cell Valley has achieved major breakthroughs in CAR-NK manufacturing processes, with significant clinical efficacy.

The study first isolated NK cells from the peripheral blood of healthy donors and induced their transformation into CIML NK cells with memory-like properties through brief activation with specific cytokines (IL-12, IL-18, and IL-15). After co-culturing CIML NK cells with EOC cell lines (OVCAR8, SKOV3, OVCAR3, CaOV3, CaOV4) for 6 hours, in vitro experiments showed enhanced cytotoxicity, degranulation (CD107a), and interferon-gamma (IFN-γ) production, indicating their potential in anti-tumor activity.

Subsequently, the research team designed a novel CAR specifically targeting the membrane-proximal domain of the MSLN protein, which is highly expressed in EOC. Using Baboon lentivirus (BaLV) mediation, they successfully transduced the MSLN-CAR gene into CIML NK cells to produce MSLN-CAR CIML NK cells. These cells demonstrated significant cytotoxicity and activation status against EOC cell lines in vitro. In in vitro experiments, MSLN-CAR CIML NK cells exhibited significant cytotoxicity against EOC cell lines (including OVCAR8, SKOV3, and OVCAR3). Compared to untransduced CIML NK cells, MSLN-CAR CIML NK cells showed higher expression of CD107a and IFN-γ after co-culture with EOC cell lines, indicating stronger anti-tumor activity.

To further validate the in vivo efficacy of MSLN-CAR CIML NK cells, researchers tested them in patient-derived xenograft (PDX) models of EOC. Results showed that MSLN-CAR CIML NK cells not only significantly inhibited tumor growth in vivo but also effectively prevented tumor metastasis. Furthermore, even in an immunosuppressive environment simulating patient ascites, these MSLN-CAR CIML NK cells were able to maintain their anti-tumor activity.

In summary, this study successfully demonstrates the significant efficacy of MSLN-CAR CIML NK cells in EOC treatment. Both in vitro and in vivo experiments showed a substantial inhibition of tumor growth and metastasis. The potential of this therapy lies not only in its direct anti-tumor effects but also in its ability to potentially overcome immunosuppression within the tumor microenvironment. This provides a new strategy and hope for EOC immunotherapy and lays the groundwork for future clinical trials and potential treatment regimens. Currently, Shenzhen Cell Valley has deployed multiple targets in fields including hematologic malignancies and solid tumors, with a reserve of over fifty tumor-associated targets. Its extensive clinical experience in CAR-T and CAR-NK therapies facilitates better clinical translation and application.