Non–Small-Cell Lung Cancer: Feasibility of Intratumoral Radiofrequency Hyperthermia–enhanced Herpes Simplex Virus Thymidine Kinase Gene Therapy

Abstract

Purpose To validate the feasibility and efficacy of intratumoral radiofrequency hyperthermia (RFH)-enhanced herpes simplex virus (HSV) thymidine kinase (TK) and ganciclovir (GCV) (hereafter, HSV-TK/GCV) gene therapy for non-small-cell lung cancer (NSCLC). Materials and Methods This study was performed from November 11, 2015, to April 14, 2017, and included (a) in vitro experiments with human NSCLC cells to establish the proof of principle, (b) in vivo experiments using mice with subcutaneous NSCLC to further demonstrate the principle, and (c) in vivo experiments using rats with orthotopic NSCLC to validate the technical feasibility. Cells, nude mice, and nude rats were randomly divided into four groups (six animals per group): (a) combination therapy (HSV-TK/GCV combined with RFH), (b) RFH, (c) HSV-TK/GCV, and (d) phosphate-buffered saline. Data were analyzed by using the Dunnett t test or Kruskal-Wallis test. Results For in vitro experiments, the cell proliferation assay showed significantly diminished viable cells with combination therapy (mean, 0.56; 95% confidence interval [CI]: 0.44, 0.68) versus RFH (mean, 0.89; 95% CI: 0.82, 0.97), HSV-TK/GCV (mean, 0.71; 95% CI: 0.56, 0.86), and phosphate-buffered saline (mean, 1; 95% CI: 1, 1) (P < .05 for all). For in vivo experiments, optical imaging showed significantly decreased relative bioluminescence signal with combination therapy (mean, 0.71 [95% CI: 0.03, 1.39] in mice; 1.29 [95% CI: 0.51, 2.06] in rats) compared with RFH (mean, 2.66 [95% CI: 1.73, 3.59] in mice; 2.26 [95% CI: 1.51, 3.01] in rats), HSV-TK/GCV (mean, 1.37 [95% CI: 0.65, 2.08] in mice; 1.76 [95% CI: 1.20, 2.31] in rats), and phosphate-buffered saline (mean, 3.07 [95% CI: 2.50, 3.65] in mice; 2.94 [95% CI: 2.29, 3.58] in rats) (P < .001 for all). US showed that the smallest relative tumor volumes occurred with combination therapy (mean, 0.60; 95% CI: 0.15, 1.05) versus RFH (mean, 2.43; 95% CI: 1.80, 3.06), HSV-TK/GCV (mean, 1.32; 95% CI: 0.75, 1.89), and phosphate-buffered saline (mean, 2.56; 95% CI: 1.75, 3.38) (P < .05 for all) in the mouse subcutaneous model. Conclusion Intratumoral radiofrequency hyperthermia-enhanced herpes simplex virus thymidine kinase and ganciclovir gene therapy for non-small-cell lung cancer is feasible and can be guided by molecular imaging. © RSNA, 2018.

WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling

“…All human tissues were obtained with written informed consents and with the approval of the Medical Ethical Committee of Sir Run Run Shaw Hospital. IHC staining was performed following our previously reported protocol [23]. The following antibodies were used for IHC staining – anti-Her-2/ErbB2 (Roche, 790–4493), anti-PR (Novocastra, NCL-L-PGR-312), anti-ER (Novocastra, NCL-L-ER-6F111), anti-Ki-67 (Dako, M7240), anti-EGFR (Roche, 790–4347), anti-CK-5/6 (Dako, M7237), anti-Wnt5b (Abcam, ab94914), and REAL™ EnVision™ Detection System, HRP/DAB, Rabbit/Mouse kit (Dako, K5007).…”

“…The mice were then imaged under 530 nm laser irradiation. Ultrasound imaging was performed following our previously reported protocol [23].…”

Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets

“…In cholangiocarcinoma bearing mice, interventional RFH treatment significantly promotes the inhibitory effects of PHSP-TK/GCV therapy evident as in vivo significant reduction in tumor size and higher apoptosis index (Luo et al., 2018). Another experiment in tumor-bearing mice or rats also showed that RFH-enhanced HSV-TK/GCV gene therapy for non-small-cell lung cancer is feasible (Ji et al., 2018). Chen and Tang found that the HSV-TK/GCV system in combination with radiotherapy also has stronger therapeutic effects on the tumor.…”

“…Researchers believe that the most clinically significant approach to combat this limitation is to develop novel gene vectors or effectively enhance the specific expression of HSV-TK by linking transcriptional regulatory elements such as tumor-specific promoters and enhancers and identifying the appropriate gene vector is also key to guaranteeing high security and efficiency in suicide gene therapy (Qiu et al., 2012; Hossain et al., 2016). Besides, combining suicide genes with classical and traditional therapeutic modalities (radiotherapy and RFH) (Chen and Tang, 2010; Ji et al., 2018), developing fusion gene therapy approaches (CD/TK), and designing therapeutic alliances with multiple gene therapies are worthy of exploration. Notably, immune genes, cytotoxic genes and tumor suppressor genes are often the mainstream choices for multi-gene combination therapy strategies, but combination therapy with silencing genes that inhibit immune function is also a feasible reverse method (Ahn et al., 2012).…”

Clinical effects of high frequency hyperthermia-assisted irinotecan chemotherapy on patients with middle and advanced colorectal cancer and its safety assessment

“…Due to its characteristics of rapid growth, the tumor tissue has disordered structure and abnormal blood vessel growth, which is often squeezed together, with slow heat dissipation. The sustained energy absorption of tumor cells causes a rapid rise in temperature, ultimately resulting in their irreversible damage and death, thereby treating tumors (10,11). However, worldwide there have been few studies related to high frequency hyperthermia combined with chemotherapy.…”