Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus

Background: Pancreatic cancer is an aggressive, immunologically “cold” tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). Methods: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). Results: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. Conclusion: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer

Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles

Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. In this study, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and they showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs

Feasibility of restorative proctocolectomy in patients with ulcerative colitis-associated lower rectal cancer: A retrospective study

Summary: Background/Objective: Restorative proctocolectomy (RP) may improve quality of life in patients with ulcerative colitis (UC)-associated lower rectal cancer to a greater extent than total proctocolectomy. However, patients with UC-associated cancer often have flat mucosal lesions that make it extremely difficult to endoscopically delineate the tumor margins. Therefore, there is a potential risk of residual tumor and local recurrence after RP in patients with UC-associated lower rectal cancer. The aim of this study was to assess the feasibility of RP in patients with UC-associated cancer of the lower rectum. Methods: We retrospectively identified nine patients who had undergone RP for UC-associated lower rectal cancer at the Niigata University Medical and Dental Hospital between January 2000 and December 2016. The incidence of flat mucosal cancer, distal margin status, and oncologic outcomes were evaluated in the nine patients. Results: Eight (89%) of the nine patients had flat mucosal cancer in the lower rectum. The median length of the distal margin was 22 mm (range 0–55 mm). No patient developed local or distant recurrence during follow-up. One patient had a positive distal margin. This patient underwent annual pouchoscopy, but had no local recurrence and died of pancreatic cancer 81 months after RP. The remaining eight patients were alive at the final observation. Five-year and 10-year overall survival rates in the nine patients were 100% and 66.7%, respectively. Conclusion: Patients with UC-associated lower rectal cancer often have lesions of the flat mucosal type. However, RP is feasible and not necessarily contraindicated in such patients. Keywords: inflammatory bowel disease, rectal cancer, restorative proctocolectomy, ulcerative colitis, ulcerative colitis-associated cance

Additional file 1: Figure S1. of Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine

Location of genetic aberrations for Japanese and US patients, and TCGA samples. Mutations in (A) APC, (B) ERBB2, (C) TP53, (D) NRAS, and (E) KRAS for Japanese patients (n = 201), US patients (n = 108), and TCGA samples (n = 224) were aligned to protein domains. The number of mutations at each given amino acid were plotted in corresponding pie graphs. As shown, KRAS G12 were the highest frequency mutations. Patient samples were further plotted by mutation status (F) KRAS-hypermutated and (G) KRAS-non-hypermutated. Figure S2. Correlation of RNF43 mutations with MMR. (A) The frequencies of APC and RNF43 mutations were determined by MMR phenotype. Statistical significance was determined by Fisher’s exact test. (B) Mutation mapper analysis identified G659 as most frequently altered in MMR-D cases. Figure S3. Gene-based statistical analysis for clinical information. Genes were filtered based on Fisher’s exact test (p < 0.05). Cell values are log odds ratios colored from blue to red. Dendrograms were created by Euclidean distance and Ward’s method. Less (blue) or more (red) aggressive factors of seven clinical variables are shown: lymphatic invasion (ly), vascular invasion (v), histopathological grade (G), TNM classifications (T, N, and M), and tumor stage. Figure S4. Cluster of 61-gene co-mutation patterns. (A) Cluster analysis was performed on non-hypermutated Japanese CRC samples (n = 184 tumors) by using Euclidean distance and Ward’s clustering method (closest distance to common mutated genes are colored yellow to blue). (B) Co-mutated gene patterns of the 61-gene set with statistical analysis. Mutation rate in each group is shown as a bar graph in the middle panel. Group-based mean values for age and tumor diameter are shown (left) with cluster colors and fraction for clinical information (right). Dark bars indicate significant difference (p < 0.05, two-tailed Fisher’s exact test) to the distribution of all other non-hypermutated donors, light bars are non-significant (**p < 0.01, *p < 0.05). Figure S5. Data complementary to Fig. 3. (A) Cluster analysis was performed on non-hypermutated Japanese CRC samples (n = 184 tumors) by using Euclidean distance and Ward’s clustering method (closest distance to common mutated genes are colored yellow to blue). (B) Kaplan–Meier survival estimates according to genomic subgroups. Overall survival was analyzed in 102 patients with Stage IV CRC treated with anti-EGFR therapies. The patients were divided to “All WT (wild type)” (Cluster 1; n = 25) or “Mutated” (Clusters 2–8; n = 77) based on the cluster analysis with targeted therapy-related 26 genes. Table S1. The 415-gene list for the CGS platform. Table S2. BRAF mutation and tumor location (J-CRC, n = 201). Table S3. Raw data for gene-based statistical analysis for clinical information. Table S4. Clinicopathological characteristics of 201 CRC patients. (PDF 1435 kb