Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody.

The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

[A Case of Inverted LECS for GIST in the Remnant Stomach after Distal Gastrectomy].

Laparoscopy and endoscopy cooperative surgery(LECS)is the surgical procedure used to avoid excessive resection of the gastrointestinal wall and preserve its function. We report the case of a patient who was successfully treated with inverted LECS for gastrointestinal stromal tumor(GIST)in the remnant stomach and underwent distal gastrectomy. The patient was a 75- year-old man who received distal gastrectomy for gastric ulcer 28 years before. Three years before he was diagnosed as having gastric submucosal tumor(SMT)as a gastrointestinal tumor(GIST)by using EUS. As the tumor increased, he was admitted to our hospital. Upper gastrointestinal endoscopy revealed a 30mm SMT just below the cardiac part of the remnant stomach. Biopsy by EUS-FNA revealed CD34(-), c-kit(+), S-100(-), and a-SMA(-), which indicated gastric GIST. Inverted LECS was performed. His postoperative course was good, and he was discharged from the hospital 9 days after the surgery.

[A Case of Gastric Small Cell Carcinoma with Rapid Regrowth after Surgery].

The patient was a 59-year-old man with type 2 advanced gastric cancer in the antrum. Abdominal computed tomography revealed the primary tumor with regional lymph node metastasis. Distal gastrectomy and D2 lymph node dissection were performed. Histopathological findings indicated gastric small cell carcinoma. Lymph node metastasis was observed microscopically in the #6 lymph nodes. Peritoneal lavage cytology was positive. The pathologic stage of the disease was pT2(MP), med, INF b, ly2, v2, pPM0, pDM0, pN2(6/33: #5, #6), M1, P0, CY1, H0, stage Ⅳ, R1(cy+). After surgery, he received chemotherapy with capecitabine plus oxaliplatin. However, after 1 course of therapy the disease had progressed, and the patient was diagnosed with peritoneal metastasis. Chemotherapy of CDDP plus CPT-11 was initiated, and after 5 courses the patient died.

HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer.

An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.

[A Case of Long-Term Disease-Free Survival of a Gastric Cancer Patient with Peritoneal Dissemination and Transverse Colon Invasion].

A 71-year-old man visited our hospital because ofepigastralgia and anorexia. Upper gastrointestinal endoscopy revealed type 1 gastric cancer. Contrast-enhanced abdominal CT revealed gastric wall thickening in the midgastric region and direct invasion ofthe transverse colon. CT findings also revealed a suspicion ofdissemination on the omentum and para-aortic lymph node swelling. We diagnosed gastric cancer with transverse colon invasion. Therefore, we performed distal gastrectomy with transverse colectomy and D2+No.16b1 lymph node dissection after obtaining patient consent. We observed direct tumor invasion into the transverse colon and seeding nodules on the omentum. Liver metastasis was not seen, and ascitic cytology was negative. He was discharged 16 days postoperatively, without any complications. Histopathological analysis revealed poorly differentiated adenocarcinoma and gastrocolic fistula. Postoperatively, S-1 was administered for 4 years as adjuvant chemotherapy. There has been no recurrence for 9 years after surgery.

[A Case of Goblet Cell Carcinoid of the Appendix Treated by Laparoscopic Ileocecal Resection after Diagnosis by Colonoscopic Examination for Positive Occult Blood].

A79 -year-old woman underwent colonoscopic examination for positive occult blood. Aneoplastic lesion was seen in the orifice of the vermiform appendix. She was referred to our hospital and underwent colonoscopic examination again. The biopsy revealed poorly differentiated adenocarcinoma or mixed adenoneuroendocrine carcinoma(MANEC), and she was diagnosed with carcinoma of the appendix. She was treated by laparoscopic ileocecal resection with lymph node dissection (D3). Histopathological examination revealed goblet cell carcinoid(GCC)of the appendix with serosal invasion. No metastasis was detected in the dissected lymph nodes. This patient has been followed-up for 6 months after surgery and no recurrences have been detected.

[A Case of Intussusception Caused by Colon Cancer in A 25-Year-Old Woman].

A 25-year-old woman presented to our hospital with left flank pain and diarrhea. Contrast-enhanced abdominal computed tomography(CT)showed a target sign in the descending colon. She was diagnosed with intussusception of the colon. Colonoscopy revealed a tumor at the splenic flexure. We performed surgery and found an invaginated transverse colon at the splenic flexure. Reduction was unsuccessful with Hutchinson's maneuver, and we performed partial resection of the invaginated colon. Histopathological diagnosis was adenocarcinoma, tub1, SM2. Adult intussusception is uncommon, especially in young adults. It is usually caused by a polyp or tumor. We report a case of intussusception caused by colon cancer in a young female patient, and review the literature.

[A Case of Long-Term Survival with Multidisciplinary Therapy for a Patient with Multiple Metastases from Rectal Cancer].

Combined modality therapy is sufficient to treat advanced rectal cancer with multiple metastases. Her, we report a case of long-term survival in a patient with multiple metastases from rectal cancer. A5 8-year-old man had previously undergone low anterior resection for advanced rectal cancer. Multiple liver and lung metastases were identified prior to operation; therefore, we initiated chemotherapy(FOLFOX). Partial resection of metastatic lesions and radiofrequency ablation(RFA)were also administered, but newly developed liver, lung, and adrenal gland metastases were identified. We changed the chemotherapy regimen and administered topical therapies(partial resection, RFA, hepatic arterial infusion chemotherapy, radiotherapy)for each chemotherapy-refractory metastatic lesion. Although the patient is in a tumor-bearing state, he is still alive 10 years after his first operation. This combined modality therapy is an option for patients with chemotherapy-refractory metastases from rectal cancer.

PD-L1 expression combined with microsatellite instability/CD8+ tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer.

While the importance of programmed death-ligand 1 (PD-L1), mutation burden caused by microsatellite instability (MSI), and CD8+ tumor infiltrating lymphocytes (TILs) has become evident, the significance of PD-L1 expression on prognosis still remains controversial. We evaluated the usefulness of combined markers of PD-L1 and MSI or CD8+ TILs as a prognostic biomarker in gastric cancer. A total of 283 patients with gastric cancer were reviewed retrospectively. PD-L1 expression on >5% tumor cells was defined as PD-L1-positive. PD-L1-positive rate was 15.5% (44/283). PD-L1 positivity was significantly correlated with invasive and advanced cancer and also significantly correlated with MSI, whereas no significance was observed with CD8+ TILs. Kaplan-Meier analysis showed that PD-L1 positivity significantly correlated with a poor prognosis (p = 0.0025). Multivariate analysis revealed that PD-L1 positivity was an independent poor prognostic factor (hazard ratio [HR]: 1.97, p = 0.0106) along with diffuse histological type and lymph node metastases. Combinations of PD-L1 and MSI (HR: 2.18) or CD8+ TILs (HR: 2.57) were stronger predictive factors for prognosis than PD-L1 alone. In conclusion, combined markers of PD-L1 and MSI or CD8+ TILs may be more useful prognostic biomarkers in gastric cancer, and better clarify the immune status of gastric cancer patients.

Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system.

Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40-50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.

Establishment of a Non-Invasive Semi-Quantitative Bioluminescent Imaging Method for Monitoring of an Orthotopic Esophageal Cancer Mouse Model.

Orthotopic models of various types of tumors are widely used in anti-tumor therapeutic experiments in preclinical studies. However, there are few ways to appropriately monitor therapeutic effect in orthotopic tumor models, especially for tumors invisible from the outside. In this study we aimed to establish a non-invasive semi-quantitative bioluminescent imaging method of monitoring an orthotopic esophageal cancer mouse model. We confirmed that the TE8 esophageal cancer cell line implanted orthotopically into the abdominal esophagus of nu/nu mice (n = 5) developed not only a main tumor at the implanted site, but also local lymph node metastases and peritoneal disseminations within 6 weeks after inoculation. We established a TE8 cell line that stably expressed the firefly luciferase gene (TE8-Luc). We showed that TE8-Luc cells implanted subcutaneously into nu/nu mice (n = 5) grew over time until 5 weeks after inoculation. Tumor volume was strongly correlated with luminescent intensity emitted from the tumor, which was quantified using the IVIS imaging system. We then showed that TE8-Luc cells implanted orthotopically into the mouse abdominal esophagus (n = 8) also formed a tumor and that the luminescent intensity of such a tumor, as detected by IVIS, increased over time until 7 weeks after inoculation and was therefore likely to reflect tumor progression. We therefore propose that this orthotopic esophageal cancer model, monitored using the non-invasive semi-quantitative IVIS imaging system, will be useful for in vivo therapeutic experiments against esophageal cancer. This experimental setting is expected to contribute to the development of novel therapeutic technologies for esophageal cancer in preclinical studies.