Anti-MUC16 monoclonal antibody, clone SW186:2

Background More favorable treatment against epithelial ovarian cancer (EOC) is urgently needed because of its insidious nature at an early stage and a low rate of five-year survival. The current primary treatment, extensive surgery combined with chemotherapy, exhibits limited benefits for improving prognosis. Chimeric antigen receptor T (CAR-T) cell technology as novel immunotherapy has made breakthrough progress in the treatment of hematologic malignancies, and there were also benefits shown in a partial solid tumor in previous research. Therefore, CAR-T cell technology may be a promising candidate as an immunotherapeutic tool against EOC. However, there are some weaknesses in targeting one antigen from the previous preclinical assay, such as on-target off-tumor cytotoxicity. The dual-target CAR-T cell may be a better choice. Methods We constructed tandem PD1-antiMUC16 dual-CAR, PD1 single-CAR, and anti-MUC16 single-CAR fragments by PCR and genetic engineering, followed by preparing CAR-T cells via lentiviral infection. The expression of CAR molecules on single and dual CAR-T cells was detected by flow cytometry. The killing capacity and activation of CAR-T cells were measured by cytotoxic assays and cytokines release assays in vitro. The therapeutic capacity of CAR-T cells was assessed by tumor-bearing mice model assay in vivo. Results We successfully constructed CARs lentiviral expression vectors and obtained single and dual CAR-T cells. CAR-T cells demonstrated robust killing capacity against OVCAR-3 cells in vitro. Meanwhile, CAR-T cells released plenty of cytokines such as interleukin-2(IL-2), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha(TNF-alpha). CAR-T cells showed a therapeutic benefit against OVCAR-3 tumor-bearing mice and significantly prolonged the survival time. Dual CAR-T cells were shown to be two to four times more efficacious than single CAR-T cells in terms of survival time. Conclusion Although exhibiting a similar ability as single CAR-T cells against OVCAR-3 cells in vitro, dual CAR-T cells demonstrated enhanced killing capacity against OVCAR-3 cells as compared to single CAR-T cells in vivo and significantly prolonged the survival time of tumor-bearing mice. PD1-antiMUC16 CAR-T cells showed more potent antitumor activity than single CAR-T cells in vivo. The present experimental data may support further research work that will have the potential to lead to clinical studies.

Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.