Nalotimagene Carmaleucel

Cholangiocarcinoma is a most lethal malignancy frequently resistant to chemotherapy. Herpes simplex virus thymidine kinase/Ganciclovir (HSV-TK/GCV) suicide gene therapy is a promising approach to treat different cancers, including cholangiocarcinoma. However drawbacks including low therapeutic gene expression and lack of precise targeted gene delivery limit the wide clinical utilization of the suicide gene therapy. We attempted to overcome these obstacles. We established the "proof-of-principle" of this concept via serial in-vitro experiments using human cholangiocarcinoma cells and then validated the new interventional oncology technique in vivo using mice harboring the same patient derived cholangiocarcinomas. Curative effects were evaluated by magnetic resonance imaging and confirmed by pathology and laboratory examinations. Intratumoral radiofrequency hyperthermia (RFH) significantly elevated the targeted expression of HSV-TK gene and further enhanced the therapeutic effects of direct intratumoral HSV-TK/GCV gene therapy, evident as the least number of survival tumor cells, smallest tumor size, and the highest apoptosis index in the combination treatment of HSV-TK plus RFH, compared to other control treatments. The novel combination of image-guided interventional oncology, RFH technology, and direct gene therapy may be valuable for the effective treatment of cholangiocarcinoma.

Herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) therapy is one of the most promising therapeutic strategies for the treatment of cholangiocarcinoma, which is the second most common hepatobiliary cancer. The aim of the present study was to evaluate the enhanced therapeutic effects of HSV-TK/GCV with gemcitabine on cholangiocarcinoma. QBC939 cholangiocarcinoma cells and mouse models of cholangiocarcinoma (established via tumor xenografts) received one of the following treatments: i) Gemcitabine therapy (3 µg/ml); ii) HSV-TK/GCV monotherapy; iii) HSV-TK/GCV + gemcitabine; and iv) control group, treated with phosphate-buffered saline. Cell proliferation was quantified using MTT assay and post-treatment tumor alterations were monitored using ultrasound imaging and optical imaging. For the in vitro experiments, the MTT assays demonstrated that the relative cell viabilities in the gene therapy, gemcitabine and gemcitabine + gene groups were 70.37±9.07, 52.64±8.28 and 34.21±6.63%, respectively. For the in vivo experiments, optical imaging indicated significantly decreased optical signals in the combination therapy group, as compared with the gemcitabine and gemcitabine + gene groups (1.68±0.74 vs. 2.27±0.58 and 2.87±0.82, respectively; Р<0.05). As demonstrated by ultrasound imaging, reduced tumor volumes were detected in the combination therapy group, as compared with the three control groups (114.32±17.17 vs. 159±23.74, 201.63±19.26 and 298.23±36.1 mm3, respectively; P<0.05). The results of the present study demonstrated that gemcitabine enhances the antitumoral effects of HSV-TK/GCV on cholangiocarcinoma, which may provide a novel therapeutic strategy for the management and treatment of cholangiocarcinoma using gemcitabine and gene therapy.