Concepts in Oncolytic Adenovirus Therapy

Oncolytic adenovirus therapy is gaining importance as a novel treatment option for the management of various cancers. Different concepts of modification within the adenovirus vector have been identified that define the mode of action against and the interaction with the tumour. Adenoviral vectors allow for genetic manipulations that restrict tumour specificity and also the expression of specific transgenes in order to support the anti-tumour effect. Additionally, replication of the virus and reinfection of neighbouring tumour cells amplify the therapeutic effect. Another important aspect in oncolytic adenovirus therapy is the virus induced cell death which is a process that activates the immune system against the tumour. This review describes which elements in adenovirus vectors have been identified for modification not only to utilize oncolytic adenovirus vectors into conditionally replicating adenoviruses (CRAds) that allow replication specifically in tumour cells but also to confer specific characteristics to these viruses. These advances in development resulted in clinical trials that are summarized based on the conceptual design.

Anti-tumour effect of neo-antigen-reactive T cells induced by RNA mutanome vaccine in mouse lung cancer

Purpose Mutation-specific T-cell response to epithelial cancers and T-cell-based immunotherapy has been successfully used to treat several human solid cancers. We aimed to investigate the anti-tumour effect of neo-antigen-reactive T(NRT) cells induced by RNA mutanome vaccine, which may serve as a feasible and effective therapeutic approach for lung cancer. Methods We predicted candidate neo-antigens according to the mutant gene analysis by sequencing the mouse Lewis cells and C57BL/6 mouse tail tissue. RNA vaccine was prepared with the neo-antigens as the template. We assessed antitumor efficacy, cytokine secretion and pathological changes after adoptive transfer of NRT cells in vitro and vivo experiments. Results We identified 10 non-synonymous somatic mutations and successfully generated NRT cells. The percentage of T-cell activation proportion was increased from 0.072% in conventional T cells to 9.96% in NRT cells. Interferon-γ secretion augmented from 17.8 to 24.2% as well. As an in vivo model, adoptive NRT cell infusion could promote active T-cell infiltration into the tumour tissue and could delay tumour progression. Conclusion NRT cells induced by RNA mutanome vaccine exert a significant anti-tumour effect in mouse lung cancer, and adoptive NRT cell therapy might be considered a feasible, effective therapeutic approach for lung cancer.

Association between time to stent dysfunction and the anti-tumour effect of systemic chemotherapy following stent placement in patients with pancreaticobiliary cancers and malignant gastric outlet obstruction: a retrospective cohort study

Background Malignant gastric outlet obstruction (MGOO) occasionally occurs due to pancreaticobiliary cancer. Endoscopic duodenal stenting (DS) is a common treatment for MGOO. However, it has been reported that DS does not have sufficient patency time for it to be used in patients who have a potentially increased lifespan. Nowadays, systemic chemotherapy for pancreaticobiliary cancer has developed, and its anti-tumour effect would make time to stent dysfunction longer. Therefore, we retrospectively evaluated the association between objective response to systemic chemotherapy, followed by DS and time to stent dysfunction in patients with advanced pancreaticobiliary cancer. Methods This retrospective study included 109 patients with advanced pancreaticobiliary cancer who received systemic chemotherapy after DS. Patients who showed complete or partial response were defined as responders. The rest were defined as non-responders. Time to stent dysfunction was compared between responders and non-responders using the landmark analysis at 2 months after DS. Death without recurrence of MGOO was considered as a competing risk for time to stent dysfunction. Results Combination and monotherapy regimens were adopted for 46 and 63 patients, respectively. Median progression-free survival and overall survival were 3.2 months (95% confidence interval [CI], 2.4–4.0) and 6.0 months (95% CI, 4.6–7.3). Objective response was observed in 21 patients (19.3%). Median time to stent dysfunction was 12.5 months (95% CI, 8.4–16.5) in the entire cohort. In 89 patients, responders had a lower cumulative incidence of stent dysfunction than non-responders: 9.5 and 19.1% at 6 months, and 19.0 and 27.9% at 1-year, respectively. There was difference of time to stent dysfunction between responders and non-responders among patients who received combination regimen as the first-line treatment with p-value of 0.009: cumulative incidence was 0 and 42.9% at 6 months, and 9.3 and 57.1% at 1-year, respectively. Conclusions Longer time to stent dysfunction is expected when systemic chemotherapy following DS suppresses tumour progression; DS is slated to be a standard treatment for MGOO even in patients with pancreaticobiliary cancer and a long lifespan.

CURCUMINE REDUCES THE GROWTH OF COLORECTAL LIVER IMPLANTS IN RATS

INTRODUCTION Some plant-based antioxidants, such as curcumin, have shown anti-tumour properties against breast carcinomas and gliomas. The aim of this piece of work is to assess the anti-tumour effect of curcumin on CC531 colorectal cancer cells, both in vitro and in vivo. MATERIAL AND METHODS On CC531 cultures, cell viability was analysed, as well as cell migration capacity (wound healing test), 24, 48 and 72 hours after treatment with curcumin (15, 20, 25 or 30 µM). Additionally, in WAG/RijHsd rats bearing CC531-induced liver implants, total and individual liver lobe tumour volume was quantified in untreated and curcumin-treated animals (200 mg/kg/day, oral). Furthermore, serum enzyme measurements (GOT, GPT, glucose, bilirubin, etc.) were carried out to assess possible effects on liver function. ANOVA and t tests were used to analyse the effects of curcumine treatment. RESULTS In vitro studies showed curcumin's greatest effects 48h after application, when all tested doses reduced cell proliferation by more than 30% (0.443±0.06 vs. 0.319±0.04, 0.302±0.06, 0.274±0.06 and 0.243±0.03, respectively; p < 0.0001). At 72 hours, the highest doses of curcumin (25 and 30 µM) reduced cell viability to less than 50%. Wound healing test also showed that curcumine also inhibits migration capacity. In vivo, curcumin reduced by 5.6 fold the tumour volume of liver implants (7.98±1.45 vs 1.41±1.33; p < 0.0001); however, the volume of healthy liver tissue was higher in untreated animals (10.91±1.01 vs 8.80±1.06; p > 0.01). CONCLUSIONS Curcumin has shown an anti-tumour effect against liver implants from colorectal cancer, both in vitro and in vivo, in this experimental model.

Anti-tumour Effect of Cyanidin-3-o-glucoside Combined With Cisplatin in the Mice Xenograft Models of Cervical Cancer

Cervical cancer is the fourth most common carcinoma in women. Cisplatin (DDP) is the first-line drug for the treatment of cervical cancer. Although efficacious, its application is constrained by the intolerance and serious adverse effects associated with cisplatin. Here, we aimed to investigate the in vivo anti-cervical cancer effects of cyanidin-3-o-glucoside (C3G), a type of anthocyanin, and DDP, when used alone or in combination; a BALB/c nude mouse xenograft tumour model was used. The tumour was inhibited in the three treatment groups when compared with untreated controls. The inhibition of tumour was 40.49%, 50.15%, and 58.49% when treated with C3G alone [40 mg/kg body weight (bw)], DDP alone (3 mg/kg bw), or a combination of C3G and DDP, respectively. Immunohistochemistry analysis indicated that treatment with C3G, DDP, or the combination induced apoptosis in xenograft tumours. Furthermore, after treatment, Bcl-2 level was decreased, Bax and cleaved caspase-3 expression was activated, and the PI3K/AKT/mTOR signalling pathway was modulated. These results suggest that the combination of C3G and DDP may have significant synergistic anti-tumour efficacy in patients; therefore, this combination therapy has great potential for the treatment of cervical cancer.

Association Between Time to Stent Dysfunction and the Anti-Tumour Effect of Systemic Chemotherapy Following Stent Placement in Patients With Pancreaticobiliary Cancers and Malignant Gastric Outlet Obstruction: A Retrospective Cohort Study

Background: Malignant gastric outlet obstruction (mGOO) occasionally occurs due to pancreaticobiliary cancer. Endoscopic duodenal stenting (DS) is a common treatment for MGOO. However, it has been reported that DS does not have a sufficient time to stent dysfunction for it to be used in patients who have a greater potential lifespan. Nowadays, systemic chemotherapy for pancreaticobiliary cancer has developed, and its anti-tumour effect would make time to stent dysfunction longer. We therefore retrospectively evaluated the association between objective response to systemic chemotherapy followed by DS and time to stent dysfunction in patients with advanced pancreaticobiliary cancer. Methods: This retrospective study included 109 patients with advanced pancreaticobiliary cancer who received systemic chemotherapy after DS. Patients who showed complete or partial response were defined as responders. The rest were defined as non-responders. Time to stent dysfunction was compared between responders and non-responders using the landmark analysis, at 2 months after DS. Death without recurrence of MGOO was considered as a censored case for time to stent dysfunction. Results: The combination and monotherapy regimens were adopted for 41 and 68 patients, respectively. Median progression-free survival and overall survival were 3.2 4 months (95% confidence interval [CI], 2.4-4.0) and 6.0 months (95% CI, 4.6-7.3). Objective response was observed in 21 patients (19.3%). Patients who received combination regimens had longer progression-free survival and higher response rate than those with monotherapy regimens; progression-free survival was 5.1 months (95% CI, 3.1-7.0) and 2.6 months (95% CI, 1.6-3.5) with a p-value of <0.001, and response rate was 39.0% and 7.4% with a p-value <0.001, respectively. Median time to stent dysfunction was 12.5 months (95% CI, 8.4-16.5) in the entire cohort. In 89 patients, responders had longer time to stent dysfunction than non-responders: 17.4 months (95% CI, 17.3-17.5) and 7.1 months (95% CI, 1.6-12.5) with a p-value of 0.031. Conclusion: Longer time to stent dysfunction is expected when systemic chemotherapy following DS suppresses tumour progression. DS is slated to be a standard treatment for MGOO, even in patients with pancreaticobiliary cancer and a long lifespan.