Injection Of OBP-301 Research Articles

Safety and dose-escalation study of a targeted oncolytic adenovirus, suratadenoturev (OBP-301), in patients with refractory advanced liver cancer: Phase I clinical trial.

459 Background: Suratadenoturev (OBP-301) is an oncolytic adenovirus that harbors a promoter of human telomerase reverse transcriptase ( hTERT) and is genetically modified to selectively replicate within and then lyse cancer cells. The aim of this study was to assess the safety and optimal dosage for intratumoral (IT) injection of OBP-301 in patients with advanced hepatocellular carcinoma (HCC). Methods: An open-label, non-comparative, phase I dose-escalation trial was performed in 20 patients who had refractory advanced HCC. OBP-301 was administered to the primary tumor using ultrasound guidance. A single IT injection of 1010 virus particles (VP) was administered to patients in the initial cohort (Cohort-1), and the subsequent single-dose cohorts received 1011 VP (Cohort-2), 1012 VP (Cohort-3), and 3×1012 VP (Cohort-4). A multiple dose cohort (Cohort-5) received 2×1012 VP × 3 times every 2 weeks. Each of the single-dose cohorts had 3 patients and there was a single escalating dose of OBP-301 from 1010 to 3×1012 VP. The multiple-dose cohort had 8 patients, and 6 of them received multiple escalating doses of 2×1012 VP ×3 times every 2 weeks. Results: There were 18 males and 2 females, and the median age was 59.39 years (range: 48.4–65.9). Patients had good tolerance of the single dose and multiple-dose regimens, and the maximum tolerated dose (MTD) was more than 6×1012 VP/patient. There was no evidence of toxicity with increasing dose, but there was a greater frequency of treatment-emergent adverse events (TEAEs) in Cohorts 4–5 than in Cohorts 1–3. The most common TEAEs related to OBP-301 were influenza-like illness (30%), pyrexia (15%), and fatigue, decreased platelet count, abdominal distension, and anemia (10% each). The overall intrahepatic mRECIST response occurred in 7 patients (39%) with confirmed stable disease (SD) and 11 (61%) with progressive disease (PD). The best target response occurred in 14 patients (78%) and 4 (22%) of them had PD. There was evidence of OBP-301 replication-dependent dissemination in the blood. Cohorts 4–5 had about 50% greater levels of CD8+ T cells in peripheral blood after OBP-301 injection. Conclusions: Multiple IT injections of OBP-301 are well-tolerated in advanced HCC. Although antitumor activity of the study medication alone would not be demonstrated obviously, SD observed as best local response was higher than as overall response. Improved anti-tumor efficacy can be achieved with adjusting viral injection volume to the target sites as well as with adopting the combination therapy with another immunothrapeutics in further study (JRCT ID: jRCT2033200223). Clinical trial information: NCT02293850.

940P Dose-escalation trial of OBP-301, novel telomerase-specific oncolytic virus in advanced hepatocellular carcinoma

OBP-301 is a novel, human telomerase reverse transcriptase gene (hTERT) promoter regulated replication-competent adenovirus. Its replication, oncolysis and dissemination are restricted to cells that express the hTERT promoter, which is highly expressed in a variety of human cancers including liver cancer. We assessed the safety and efficacy of intratumoral (IT) injection of OBP-301 in advanced hepatocellular carcinoma (HCC).

Abstract CT185: Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (telomelysin) with radiotherapy in esophageal cancer patients unfit for standard treatments

Abstract Background: OBP-301 (telomelysin) is an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase (hTERT) promoter to regulate viral replication. OBP-301 causes selective replication and lysis of a variety of cancer cells, and a phase I study has confirmed the safety and biological activity of OBP-301 alone in patients with advanced solid tumors in the US. We have also completed the preclinical study demonstrating that OBP-301 inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. To further determine the feasibility, efficacy, and pharmacokinetics of OBP-301 in combination with radiotherapy, a clinical trial was designed in esophageal cancer patients unfit for standard treatments such as in elderly.Methods: An open-label, phase I dose-escalation study of OBP-301 with radiotherapy (UMIN 000010158) was conducted in 13 histologically confirmed esophageal cancer patients who deemed unfit to receive standard surgery or chemotherapy. Study treatment consisted of intratumoral OBP-301 injections on days 1, 18, and 32 of treatments. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. Virus administration was performed by intratumoral needle injection of the primary tumor through a flexible endoscope. Patients were also monitored for virus distribution and shedding into the body fluids. The primary and secondary end points were incidence of dose-limiting toxicities and objective response rate.Results: Of 13 patients, 7, 3, and 3 patients were treated in the cohorts with 10e10, 10e11, and 10e12 virus particles (vp) of OBP-301, respectively. The patients comprised 10 males and 3 females, with median age of 79.7 years (range, 53 to 92 years). Common grade 1 and 2 toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux. All patients developed a transient, self-limited lymphopenia. Distribution studies revealed that viral DNA was detected in 5 out of 6 patents received with10e11 and 10e12 vp of OBP-301, but rarely in the gargle, saliva, and urine. Eight patients had local complete response (CR); all of them exhibited pathologically no viable malignant cells in biopsy specimens, and 3 had partial response. The objective response rate was 84.6%. The clinical CR rate was 80.0% in stage I and 66.7% in stage II/III, respectively. Histopathologic examination in post-treatment specimens showed massive infiltration of CD8+ cells in 3 partially responded tumors.Conclusions: Multiple courses of endoscopic OBP-301 injection with radiotherapy were feasible and provided definite clinical benefits in patients with esophageal cancer, especially who are unfit for standard treatments. Citation Format: Toshiyoshi Fujiwara, Shunsuke Tanabe, Hiroshi Tazawa, Nobuhiko Kanaya, Kazuhiro Noma, Shunsuke Kagawa, Shinji Kuroda, Yasuo Urata, Yasuhiro Shirakawa. Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (telomelysin) with radiotherapy in esophageal cancer patients unfit for standard treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT185.

Abstract 4851: Involvement of extracellular vesicles in the abscopal effect induced by oncolytic adenovirotherapy

Abstract Background: The abscopal effect is a phenomenon that shrinkage of metastatic tumors occurs concurrently with shrinkage of primary tumors by local treatments such as radiotherapy, and is generally considered to be caused through activation of the immune system. Extracellular vesicles (EVs) are recent interesting topics in scientific fields and are known to play important roles in a variety of intercellular communication processes including immune response. We previously developed a telomerase specific oncolytic adenovirus, Telomelysin (OBP-301), which is currently being tested in clinical trials, and have sometimes observed therapeutic effects on metastatic tumors after local injection to primary tumors in immunodeficient mouse models. Here, we hypothesized that EVs derived from OBP-301-treated tumors may be associated with the abscopal effect of OBP-301. Methods: A human colon carcinoma cell line HCT116 and HCT116 expressing RFP (HCT116-RFP) were used in this study. EVs were isolated by ultracentrifugation from HCT116 cells treated with OBP-301 (Exo-301). Intercellular communication and cytotoxic activity via EVs after OBP-301 treatment were assessed in a non-contact co-culture system in vitro and a bilateral subcutaneous tumor mouse model in vivo. Results: Exo-301 showed potent cytotoxic effects on HCT116 cells and this cytotoxicity was significantly blocked in the presence of anti-CD9 antibody, which suggested that Exo-301, not OBP-301 itself, was involved in this cytotoxicity. In non-contact co-culture experiments, more RFP was taken up into HCT116 cells after OBP-301 treatment on HCT116-RFP cells than control treatments, which meant that EVs including RFP reached HCT116 cells through membrane after OBP-301 treatment on HCT116-RFP cells. In a HCT116 bilateral subcutaneous tumor model in BALB/c nude mice, intratumoral injection of OBP-301 significantly suppressed the growth of untreated tumors as well as treated tumors, and in a bilateral tumor model with HCT116 on one side and HCT116-RFP on the opposite side, immunohistochemical staining showed the presence of RFP in untreated HCT116 tumors after OBP-301 treatment on HCT116-RFP tumors. These findings suggested that EVs derived from OBP-301-treated tumors was possibly involved in some cytotoxic effects on the opposite untreated tumors. Conclusion: EVs may be an important factor in the abscopal effect brought by local treatment of OBP-301 besides immune activation. Citation Format: Yoshihiko Kakiuchi, Shinji Kuroda, Nobuhiko Kanaya, Kento Kumon, Tomoko Tsumura, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara. Involvement of extracellular vesicles in the abscopal effect induced by oncolytic adenovirotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4851.

Phase II study of a telomerase-specific oncolytic adenovirus (OBP-301, Telomelysin) in combination with pembrolizumab in gastric and gastroesophageal junction adenocarcinoma.

TPS4145 Background: Although checkpoint inhibitors (CPIs) can produce durable responses in gastric cancer patients (pts) in the 3rd line setting, the response rate is only 10-15%. Therefore, there is a huge unmet need to enhance the response rate of CPIs to provide benefit to wide range of pts. A novel concept in immuno-oncology is the use of cancer specific oncolytic viral therapy. In addition to the specific killing of the tumor by the virus, these agents can induce an immunogenic cell death in the tumor to augment the immune activation driven by PD-1 inhibition. OBP-301 is an oncolytic adenovirus genetically modified to be able to selectively replicate in cancer cells by introducing human telomerase reverse transcriptase (hTERT) promoter. Results of a phase I study of OBP-301 in solid tumor pts demonstrated the safety and efficacy of intra-tumoral injection of OBP-301. A pre-clinical study of the combination of OBP-301 with anti-PD-1 antibody has also shown significant synergistic activity as well. Based on these encouraging pre-clinical and clinical data, we designed a phase II clinical trial to examine the safety and efficacy of combination of pembrolizumab and OBP-301 in the treatment of PD-L1 positive metastatic gastric/GEJ adenocarcinoma. Methods: This is a multicenter, non-randomized phase II trial of OBP-301 with pembrolizumab in metastatic gastric/GEJ adenocarcinoma that has progressed on at least 2 lines of prior therapy. Eligibility criteria include PD-L1 positive tumors as defined by a combined positive score, performance status ≤1, and good end organ function. The primary endpoints are to examine objective response rate and safety of OBP-301 with pembrolizumab. The secondary endpoints are to examine disease control rate, duration of response, overall survival and progression free survival. Correlative studies are planned to identify biomarkers for response to combination therapy by using multiparameter flowcytometry, single-cell transcriptional profiling and immunohistochemistry. All eligible pts will receive 1x1012Viral Particles/mL of OBP-301 administered every 2 weeks for total of 4 injections, injected directly into tumor via upper endoscopy. Every pt will also receive pembrolizumab 200 mg IV every 3 weeks for 2 years or until progression. Pts will be enrolled in a Simon two stage design, with 18 pts in the first stage. If 3 or more pts respond to the combination therapy, the study will move forward to stage 2, with 19 more pts enrolled. The study is currently enrolling pts.

Endoscopic intratumoral injection of OBP-301 (telomelysin) with radiotherapy in esophageal cancer patients unfit for standard treatments.

130 Background: OBP-301 (telomelysin) is an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase (hTERT) promoter to regulate viral replication. OBP-301 causes selective replication and lysis of a variety of cancer cells, and also inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. We aimed to assess intratumoral injection of OBP-301 with radiotherapy in esophageal cancer patients unfit for standard treatments. Methods: An open-label, phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed esophageal cancer patients who deemed unfit to receive surgery or chemotherapy. Study treatment consisted of intratumoral OBP-301 injections on days 1, 18, and 32 of treatment. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. Virus administration was performed by intratumoral needle injection of the primary tumor through a flexible endoscope. The primary and secondary end points were incidence of dose-limiting toxicities and objective response rate. Results: Of 13 patients, seven, three, and three patients were treated in the cohorts with 1010, 1011, and 1012 virus particles of OBP-301, respectively. The patients comprised 10 males and 3 females, with median age of 79.7 years (range, 53 to 92 years). Common grade 1 and 2 toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux. All patients developed a transient, self-limited lymphopenia. Eight patients had local complete response (CR); all of them exhibited pathologically no viable malignant cells in biopsy specimens, and three had partial response. The objective response rate was 84.6%. The clinical CR rate was 80.0% in stage I and 66.7% in stage II/III, respectively. Histopathologic examination in post-treatment specimens showed massive infiltration of CD8+ cells in three partially responded tumors. Conclusions: Multiple courses of endoscopic OBP-301 injection with radiotherapy were feasible and provided definite clinical benefits in patients with esophageal cancer. Clinical trial information: 000010158.

Abstract 4976: Telomerase-specific replication-selective virotherapy combined with radiation therapy for oral squamous cell carcinoma cells

Abstract Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We previously, investigated the antitumor effect of the hTERT-specific replication-competent adenovirus (Telomelysin: OBP-301) on oral squamous cell carcinoma (OSCC) cells in vitro and in vivo orthotopic graft model. OBP-301 replicated efficiently and induced more over 50% cell killing in a panel of human OSCC cell lines, but not in normal human fibroblasts, which were lacking telomerase activity. In orthotopic graft model, intratumoral injection of OBP-301 resulted in a significant inhibition of tumor growth and prolongation of survival. Moreover, OBP-301 in use has limited potency when administered alone; however, combination therapy using these agents and conventional anticancer agents, such as radiation exhibits encouraging levels of efficacy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301. This combination therapy was more effective compared with OBP-301 alone in OSCC cells. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human oral cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4976. doi:1538-7445.AM2012-4976

Abstract 5415: Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas

Abstract Purpose: Bone and soft tissue sarcomas frequently occur in young children and show aggressive progression, resistance to conventional chemotherapy and poor prognosis, indicating a requirement for novel antitumor therapy to improve the clinical outcome. Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor, but not of normal, cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that non-epithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear if OBP-301 is cytopathic for non-epithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells. Experimental Design: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bones (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1 and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1 and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified-OBP-301, (OBP-405), was used to confirm an antitumor effect on OBP-301-resistant sarcomas. Results: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression, not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells. Conclusions: We showed that OBP-301 has antitumor effects on both non-ALT-type and ALT-type sarcoma cells through upregulation of human telomerase reverse transcriptase mRNA. Furthermore, coxsackie and adenovirus receptor-negative sarcoma cells were efficiently killed by fiber-modified OBP-301-derived-OBP-405 through virus-integrin binding. A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5415. doi:10.1158/1538-7445.AM2011-5415

Telomerase-specific oncolytic virotherapy for human gastrointestinal cancer

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85% of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (OBP-301), in which the hTERT promoter element drives the expression of E1 genes. Since only tumor cells that express telomerase activity are able to activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. In this article we show that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human gastrointestinal malignancies.