Clinical Efficacy and Safety of AdV-tk Gene Therapy for Patients with Cervical Squamous Intraepithelial Lesion: A Prospective Study.

Cervical cancer is the fourth most common type of cancer for women in 2020, and many more women have cervical precancerous lesion-squamous intraepithelial lesion (SIL). Early treatment of cervical SIL to reverse or delay its progression is an important approach to reduce the incidence of cervical cancer. The efficacy and safety of adenovirus-based vectors expressing the thymidine kinase gene (AdV-tk) in the treatment of multiple types of cancers shows promise for its use in gynecology. We aim to provide relevant clinical efficacy and safety data after introducing AdV-tk for the treatment of cervical SIL for the first time through this prospective study. We conducted a maximum of 6 sessions to administer AdV-tk gene therapy to 23 patients (mean age: 35 years old) with cervical low-/high-grade SIL (LSIL/HSIL) who were enrolled from August 2015 to April 2018 and analyzed the clinical characteristics and follow-up outcomes (mean follow-up period: 7.3 months). The present study consisted of 17 patients (73.9%) with cervical HSIL and 6 patients with LSIL confirmed by colposcopy-directed biopsy. We observed an overall histological remission and regression rate of 87.0% (20/23, 95% confidence interval [95% CI]: 73.2-100, p < 0.001) after AdV-tk gene therapy. Eight patients (34.8%) were detected with human papillomavirus (HPV) 16/18 subtypes and 13 patients were found to be positive with at least one of the other 13 high-risk HPV (HR-HPV) subtypes, while 2 patients did not have any of the 15 HR-HPV subtypes. The overall clearance rate of HR-HPV was 76.2% (16/21, 95% CI: 58.0-94.4, p = 0.016) after AdV-tk gene therapy. For safety evaluation, no severe complications were reported in any of the 23 patients. The most commonly reported symptom was fever in 52.2% (12/23) of patients and all symptoms were fully resolved after symptomatic treatment. Our data indicate that AdV-tk gene therapy has high efficacy and safety in the treatment of cervical SIL among gynecological patients. Our findings provide clinical evidence on the potential promotion and application of AdV-tk in the treatment of cervical SIL, and potentially for cervical cancer, among gynecological patients.

The clinical course and management of cervical cancer with splenic metastasis: Case report and review of the literature.

Adenovirus-mediated herpes simplex virus thymidine kinase gene therapy (ADV-TK) in combination with interventional treatment could relieve the symptoms in patients with widespread splenic metastasis.

Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma.

Background: Combined immunotherapy approaches are promising cancer treatments. We evaluated anti-programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation. Methods: The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry. Results: GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti-PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti-PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti-PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1-mediated inhibitory signals, and GMCI improves anti-PD-1 efficacy by increasing tumor-infiltrating T-cell activation. Conclusions: Our data show that the GMCI/anti-PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.

Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma.

BACKGROUND: This randomized, open-label, multicenter, phase II clinical trial was conducted to assess the anti-tumor efficacy and safety of replication-deficient adenovirus mutant thymidine kinase (ADV-TK) in combination with ganciclovir administration in patients with recurrent high-grade glioma (HGG). PATIENTS AND METHODS: 53 patients with recurrent HGG were randomly allocated to receive intra-arterial cerebral infusion of ADV-TK or conventional treatments. The primary end point was 6-month progression-free survival (PFS-6). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and clinical benefit. This trial is registered with Clinicaltrials.gov, NCT00870181. RESULTS: In ADV-TK group, PFS-6 was 54.5%, the median PFS was 29.6 weeks, the median OS was 45.4 weeks, and better survivals were achieved when compared with control group. The one-year PFS and OS were 22.7% and 44.6% in ADV-TK group respectively, and clinical benefit was 68.2%. There are 2 patients alive for more than 4 years without progression in ADV-TK group. In the subgroup of glioblastoma received ADV-TK, PFS-6 was 71.4%, median PFS was 34.9 weeks, median OS was 45.7 weeks respectively, much better than those in control group. The one-year PFS and OS were 35.7% and 50.0% in ADV-TK group respectively. ADV-TK/ganciclovir gene therapy was well tolerated, and no treatment-related severe adverse events were noted. CONCLUSION: Our study demonstrated a notable improvement of PFS-6, PFS and OS in ADV-TK treated group, and the efficacy and safety appear to be comparable to other reported treatments used for recurrent HGG. ADV-TK gene therapy is therefore a valuable therapeutic option for recurrent HGG.