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.

Perioperative and Postoperative Continuous Nutritional Counseling Improves Quality of Life of Gastric Cancer Patient Undergoing Gastrectomy.

Post-gastrectomy syndrome (PGS) and body weight loss (BWL) decrease quality of life (QOL) and survival of the patient undergoing gastrectomy. We have introduced perioperative and post-discharge continuous nutritional counseling (CNC) to prevent BWL and improve QOL after gastrectomy. In the present study, we evaluated the effect of CNC on QOL using the Post-gastrectomy Syndrome Assessment Scale-45 (PGSAS-45). Eighty-three patients with gastric cancer (GC) who underwent curative gastrectomy between March 2018 and July 2019 were retrospectively analyzed. Patients received either pre-discharge nutritional counseling alone (control group, n = 45) or CNC (CNC group, n = 38) after gastrectomy. QOL at 12 months after gastrectomy was compared between the two groups. In QOL assessment, change in body weight (-7.98% vs. -12.77%, p = 0.0057), ingested amount of food per meal (7.00 vs. 6.07, p = 0.042) and ability for working (1.89 vs. 2.36, p = 0.049) were significantly better in CNC group than control group. Multiple regression analysis showed that CNC was a significantly beneficial factor for abdominal pain subscale (p = 0.028), diarrhea subscale (p = 0.047), ingested amount of food per meal (p = 0.012), Ability for working (p = 0.031) and dissatisfaction at the meal (p = 0.047). Perioperative and postoperative CNC could improve QOL in the patient undergoing gastrectomy in addition to preventing postoperative BWL.

p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression.

Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.

Large Tissue Debris Causing Cerebral Embolism After Transcatheter Aortic Valve Replacement.

Cerebral vascular embolism is one of the complications of transcatheter aortic valve replacement (TAVR). Thrombolytic therapy is not expected to be effective when embolic material consists of a large tissue fragment. Instead, mechanical aspiration may be more effective therapy for acute cerebral infarction after TAVR. Here, we describe the case of an 87-year-old woman with aortic valve stenosis and heart failure who underwent TAVR using a self-expandable valve. Acute cerebral infarction with left middle cerebral artery occlusion caused by a large tissue fragment developed after the procedure.

Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

Locally Advanced Rectal Cancer Invading the Gluteus Maximus Muscle Completely Responded to Total Neoadjuvant Therapy.

A 70-year-old male with anal pain and fever was diagnosed with rectal cancer perforation and abscess in the right gluteus maximus (GM) muscle. He underwent a transverse colon colostomy followed by preoperative capecitabine+oxaliplatin. Some local control was achieved but a residual abscess was observed in the right GM muscle. To secure circumferential resection margin by tumor reduction, he received chemoradiotherapy as total neoadjuvant therapy (TNT) and underwent laparoscopic abdominoperineal resection, D3 lymph node dissection, combined coccyx resection, and partial resection of the right GM muscle. The skin defect and pelvic dead space were filled with a right lateral vastus lateral great muscle flap. Histopathologically, the resected specimen showed no tumor cells in the primary tumor or lymph nodes, indicating a pathological complete response (pCR). This case suggests that TNT might improve the R0 resection and pCR rates and overall survival.

A Case Report of Non-typical Annular Pancreas Diagnosed during Laparoscopic Gastric Surgery.

An annular pancreas is a rare anomaly of the pancreas, defined as pancreatic tissue that totally or partly encircles the duodenum, usually the descending portion. A 76-year-old man who was diagnosed with gastric cancer cT3N0M0 Stage IIB underwent laparoscopic distal gastrectomy with D2 lymph node dissection. Intraoperatively, the dorsal half of the duodenal bulb was seen to be half surrounded by the pancreas, and a non-typical annular pancreas was diagnosed. Because of the risk to the pancreas, it was considered impossible to perform anastomosis by a linear stapler as in the usual laparoscopic procedure. Therefore, we performed laparoscopically assisted distal gastrectomy and Billroth-I reconstruction using a circular stapler, and the surgery was completed without difficulties. His postoperative course was good despite the development of a pancreatic fistula, which was an International Study Group for Pancreas Fistula biochemical leak. Some APs can be diagnosed preoperatively, but the rarer subtypes such as ours are more difficult to visualize on imaging. In gastrectomy, it is both oncologically important and technically challenging to perform lymph node dissection around the pancreas. In this case with an especially proximal pancreas, a circular stapler was considered better suited for gastroduodenal anastomosis and required a broader field than that afforded by laparoscopy. A case of non-typical annular pancreas diagnosed during laparoscopic gastric surgery is described.

[Therapeutic Effect of Oncolytic Adenovirus on Pancreatic Cancer Stroma].

Pancreatic ductal adenocarcinoma(PDAC)is lethal malignancy with abundant stroma. Cancer-associated fibroblasts (CAFs) exist in the PDAC stroma and contribute to progression of malignant transformation, treatment resistance, and recurrence. However, effective treatment to control PDAC stroma has not been established. We have developed tumor suppressor gene p53-armed oncolytic adenovirus(OBP-702), and have clarified therapeutic effects on PDAC cells. In this study, we investigate the therapeutic effect of OBP-702 on PDAC CAF.

Tumor-targeted fluorescence labeling systems for cancer diagnosis and treatment.

Conventional imaging techniques are available for clinical identification of tumor sites. However, detecting metastatic tumor cells that are spreading from primary tumor sites using conventional imaging techniques remains difficult. In contrast, fluorescence-based labeling systems are useful tools for detecting tumor cells at the single-cell level in cancer research. The ability to detect fluorescent-labeled tumor cells enables investigations of the biodistribution of tumor cells for the diagnosis and treatment of cancer. For example, the presence of fluorescent tumor cells in the peripheral blood of cancer patients is a predictive biomarker for early diagnosis of distant metastasis. The elimination of fluorescent tumor cells without damaging normal tissues is ideal for minimally invasive treatment of cancer. To capture fluorescent tumor cells within normal tissues, however, tumor-specific activated target molecules are needed. This review focuses on recent advances in tumor-targeted fluorescence labeling systems, in which indirect reporter labeling using tumor-specific promoters is applied to fluorescence labeling of tumor cells for the diagnosis and treatment of cancer. Telomerase promoter-dependent fluorescence labeling using replication-competent viral vectors produces fluorescent proteins that can be used to detect and eliminate telomerase-positive tumor cells. Tissue-specific promoter-dependent fluorescence labeling enables identification of specific tumor cells. Vimentin promoter-dependent fluorescence labeling is a useful tool for identifying tumor cells that undergo epithelial-mesenchymal transition (EMT). The evaluation of tumor cells undergoing EMT is important for accurately assessing metastatic potential. Thus, tumor-targeted fluorescence labeling systems represent novel platforms that enable the capture of tumor cells for the diagnosis and treatment of 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.

Surgical technique of suprapancreatic D2 lymphadenectomy focusing on the posterior hepatic plexus for advanced gastric cancer.

PURPOSE: Although D2 lymphadenectomy is currently considered a standard procedure for advanced gastric cancer (GC) worldwide, there is room for discussion about the appropriate range of suprapancreatic D2 lymphadenectomy. Focusing on the posterior hepatic plexus (PHP), which is not well recognized, we developed a surgical technique of suprapancreatic D2 lymphadenectomy, which we have called PHP-D2, and its short-term and long-term efficacies were evaluated in comparison with non-PHP-D2. METHODS: GC patients who underwent distal gastrectomy with D2 lymphadenectomy between July 2006 and May 2013 were enrolled, from which patients who had peritoneal metastasis and/or were peritoneal cytology-positive during surgery were excluded. Their medical records were retrospectively reviewed. RESULTS: Ninety-two patients (non-PHP-D2: 48, PHP-D2: 44) were enrolled. Shorter operation time (330 min vs 275 min, p < 0.0001) and less blood loss (290 mL vs 125 mL, p < 0.0001) were observed in PHP-D2, and no pancreatic fistulas were observed in PHP-D2. More lymph nodes of #11p (1 vs 1.5, p = 0.0328) and #12a lymph nodes (0 vs 1, p = 0.0034) were retrieved in PHP-D2, with no significant differences in #8a and #9 lymph nodes. Lymphatic recurrence was significantly less in PHP-D2 (p = 0.0166), and univariate and multivariate analyses showed that non-PHP-D2 was a significant risk factor for lymphatic recurrence (p = 0.0158), although there were no significant differences between non-PHP-D2 and PHP-D2 in 5-year overall survival and 5-year relapse-free survival. CONCLUSION: PHP-D2 was a safe and feasible procedure that had the potential to reduce lymphatic recurrence, and it can be a standard procedure of D2 lymphadenectomy for advanced GC.

Clinical and echocardiographic differences in three different etiologies of severe mitral stenosis.

BACKGROUND: In our institute, the causes of mitral stenosis (MS) are generally categorized into three main etiologies-rheumatic MS (RMS), degenerative MS with annular and leaflet calcification, and post-clip MS as a consequence of transcatheter mitral valve repair with clips for treating mitral regurgitation. However, clinical differences among the three etiologies are uncertain. METHODS: We retrospectively assessed 293 consecutive patients (53 with RMS, 118 with degenerative MS, and 122 with post-clip MS) who had a three-dimensional (3D) transesophageal echocardiography (TEE) derived mitral valve orifice area (MVA) of ≤1.5 cm2 , and a mean transmitral pressure gradient of ≥5 mmHg on transthoracic echocardiography. RESULTS: Although there was no difference in 3D-TEE-derived MVA among the three groups, patients with post-clip MS had a significantly lower mean transmitral pressure gradient compared to those with either of the other two types of MS (10.8 ([7.9-15.2] mmHg vs. 9.6 [7.3-12.5] mmHg vs. 6.9 [6.0-9.2] mmHg; p < .001). Patients with RMS had a higher prevalence of dyspnea. The independent determinants of dyspnea were pressure half time in RMS, 3D-TEE-derived MVA and estimated right atrial pressure in degenerative MS, and left ventricle ejection fraction in post-clip MS. CONCLUSIONS: Patients with post-clip MS had the lowest mean transmitral pressure gradient, and patients with RMS had the highest prevalence of dyspnea, despite having a similar 3D-TEE-derived MVA. The determinants of dyspnea were different among the three etiologies of MS.

Involvement in the tumor-infiltrating CD8+ T cell expression by the initial disease of remnant gastric cancer.

BACKGROUND: Remnant gastric cancer (RGC) has been increasing for various reasons such as a longer life span, medical progress, and others. It generally has a poor prognosis, and its mechanism of occurrence is unknown. The purpose of this study was to evaluate the clinicopathological features of and clarify the oncological features of RGC. METHODS: Between January 2002 and January 2017, 39 patients with RGC following distal gastrectomy underwent curative surgical resection at the Okayama University Hospital; their medical records and immunohistochemically stained extracted specimens were used for retrospective analysis. RESULTS: On univariate analysis, initial gastric disease, pathological lymph node metastasis, and pathological stage were the significant factors associated with poor overall survival (p=0.014, 0.0061, and 0.016, respectively). Multivariate analysis of these 3 factors showed that only initial gastric disease caused by malignant disease was an independent factor associated with a poor prognosis (p=0.014, hazard ratio: 4.2, 95% confidence interval: 1.3-13.0). In addition, tumor-infiltrating CD8+ T cells expression was higher in the benign disease group than in the malignant group (p=0.046). CONCLUSIONS: Initial gastrectomy caused by malignant disease was an independent poor prognostic factor of RGC, and as one of the causes, lower level of tumor-infiltrating CD8+ T cells in RGC may involve in.

Overexpression of Adenovirus E1A Reverses Transforming Growth Factor-ß-induced Epithelial-mesenchymal Transition in Human Esophageal Cancer Cells.

The epithelial-mesenchymal transition (EMT), a normal biological process by which epithelial cells acquire a mesenchymal phenotype, is associated with migration, metastasis, and chemoresistance in cancer cells, and with poor prognosis in patients with esophageal cancer. However, therapeutic strategies to inhibit EMT in tumor environments remain elusive. Here, we show the therapeutic potential of telomerase-specific replication- competent oncolytic adenovirus OBP-301 in human esophageal cancer TE4 and TE6 cells with an EMT phenotype. Transforming growth factor-ß (TGF-ß) administration induced the EMT phenotype with spindleshaped morphology, upregulation of mesenchymal markers and EMT transcription factors, migration, and chemoresistance in TE4 and TE6 cells. OBP-301 significantly inhibited the EMT phenotype via E1 accumulation. EMT cancer cells were susceptible to OBP-301 via massive autophagy induction. OBP-301 suppressed tumor growth and lymph node metastasis of TE4 cells co-inoculated with TGF-ß-secreting fibroblasts. Our results suggest that OBP-301 inhibits the TGF-ß-induced EMT phenotype in human esophageal cancer cells. OBP-301-mediated E1A overexpression is a promising antitumor strategy to inhibit EMT-mediated esophageal cancer progression.

[The Chugoku-Shikoku GanPro Produces Advanced Cancer Specialists to Provide Whole Person Medical Care].

The 3rd Chugoku-Shikoku GanPro has set a plan to train advanced cancer specialists to provide whole person medical care, and 11 partner universities have formed a consortium, and 18 working groups have been working to provide graduate school education. Through a unique e-learning system and an exercise to learn team medicine, we trained medical professionals who have advanced expertise and can provide cancer care through multidisciplinary team medicine. The project has produced a wide range of personnel including doctors, dentists, pharmacists, nurses, radiologists, medical physicists, and nutritionists. The graduates who have acquired various specialized cancer qualifications practice at regional cancer treatment centers, contributing to the enhancement and improvement of cancer treatment in the Chugoku and Shikoku regions.

[Telomerase-Specific Oncolytic Adenovirus Expressing p53 Gene Stimulating CD8+ Memory T Cells in Pancreatic Cancer].

Pancreatic cancer has poor prognosis despite the various developed multimodal treatment strategies. Currently, neoadjuvant chemotherapy and immunotherapy have attracted substantial attention as effective treatment strategies. However, amplifying immune response with existing treatments is difficult. We developed telomerase-specific oncolytic adenoviruses (OAs), including OBP-301 that is currently tested in a clinical trial of combined anti-PD-1 antibody and p53-armed OBP- 301 variant(OBP-702). OAs have immune-modulation functions and induce CD8+ T cells into tumors by releasing immunogenic cell death markers, such as extracellular adenosine triphosphate. Here, we investigated the effectiveness of OBP- 702 in pancreatic cancer treatments, focusing on the influence on CD8+ memory T cells.

Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma.

Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins αvß3 and αvß5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins αvß3 and αvß5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+ T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.

Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation.

BACKGROUND: Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. METHODS: The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. RESULTS: Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. CONCLUSION: EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.

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.

Long-term Survival with a Rare Advanced Primary Gastrointestinal Malignant Melanoma Treated with Laparoscopic Surgery/Immune Checkpoint Inhibitor.

Targeted therapies for malignant melanoma have improved patients' prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma.