Combination therapy with IFN expressing oncolytic adenovirus for pancreatic cancer

表达 IFN 的溶瘤腺病毒联合治疗胰腺癌

• 批准号: 10555328
• 负责人: Julia Davydova
• 金额: $ 34.52万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555328
• 关键词: Adenoviruses; Adjuvant Therapy; Affect; Blood Vessels; Cancer Diagnostics; Cancer Etiology; Cell Line; Cessation of life; Chemotherapy and/or radiation; Clinical; Combined Modality Therapy; Contralateral; Development; Diagnosis; Disease; Dropout; Excision; Goals; Hamsters; Human; Immune; Immunity; Immunocompetent; Immunologics; Immunotherapy; Impairment; In Vitro; Induction of Apoptosis; Interferon alpha; Interferons; Investigational Drugs; Localized Disease; Location; Longterm Follow-up; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Neoadjuvant Therapy; Neoplasm Metastasis; Nodule; North America; Oncolytic; Operative Surgical Procedures; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Phase I Clinical Trials; Principal Investigator; Prognosis; Recording of previous events; Regimen; Reporting; Resectable; Site; Slice; System; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Transgenes; Tumor Antigens; Tumor Debulking; Tumor Immunity; Unresectable; Virus; Virus Replication; Work; advanced pancreatic cancer; anti-tumor immune response; antitumor effect; cancer cell; chemoradiation; clinical application; clinical translation; cytokine; design; effective therapy; experimental study; immunogenic cell death; immunoregulation; improved; interferon therapy; new combination therapies; novel; novel therapeutics; oncolysis; oncolytic adenovirus; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; patient prognosis; selective expression; success; systemic toxicity; transgene expression; tumor; tumor xenograft

Pancreatic cancer is the 3rd leading cause of cancer-related death in North America. Most pancreatic ductal adenocarcinoma (PDAC) patients are diagnosed at an advanced stage of the disease, and treatment at these late stages is extremely challenging. Novel therapeutics for the treatment of advanced PDAC are desperately needed. In this project, we plan to develop combination therapy with interferon-expressing oncolytic adenovirus (IFN- OAd) and chemoradiation for locally advanced and unresectable pancreatic cancer (LAPC) including borderline resectable pancreatic cancer (BRPC), which constitute more than 50% of the PDAC patients. Treatment of local disease in these groups will benefit the resectability and prognosis. We have been developing oncolytic adenoviruses (OAds) as cancer therapeutics. OAds are designed to selectively replicate and spread within the tumor, resulting in a strong oncolytic effect mediated by the cytocidal function of the virus leading to immunogenic cell death. OAds can also induce massive and selective expression of a transgene in the target cancer cells where viral replication is taking place. Therefore, OAd system will be exploited to overcome the current obstacles of IFN-based therapy by selectively expressing a massive amount of IFN in the tumor region. In our preliminary experiments, IFN- expressing OAd (IFN-OAd) showed impressive tumor regression in a syngeneic PDAC model in immunocompetent hamsters, and its effect was greatly enhanced when combined with chemoradiation. We have also reported shrinkage induced by IFN-expressing Ad not only in the injected tumor but also in the untreated contralateral tumor caused by the stimulation of systemic immunity. These suggest that this new combination therapy may realize a more effective treatment of locally advanced and metastatic diseases. Toward this goal, we will first analyze the effects of the combination therapy in human PDAC cell lines and the tissue-slice culture system. We then will optimize chemoradiation regimens in order to maximize the effect of the combination therapy with IFN-OAd in an immunocompetent syngeneic hamster model. The immunological effect and toxicity of the combination therapy will also be examined rigorously. Finally, the therapeutic benefit of the novel combination approach of IFN-OAd with chemoradiaion will be analyzed in LAPC models as well as with patient-derived tumor xenografts. This project will establish a therapeutic regimen of the novel IFN-OAd-based chemoradiation in order to commence clinical translation in LAPC and BRPC patients. We have a strong team with a history of success in bringing such therapeutics to patients, andonce implemented, the therapeutic/treatment will provide an excellent opportunity to improve the current devastating clinical outcome of pancreatic cancers.

胰腺癌是北美癌症相关死亡的第三大原因。大部分胰导管

项目成果

Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer.

• DOI: 10.3390/v15040901
• 发表时间: 2023-03-31
• 期刊: Viruses
• 作者: Gavrikova T;Nakamura N;Davydova J;Antonarakis ES;Yamamoto M
• 通讯作者: Yamamoto M

Development of Oncolytic Vectors Based on Human Adenovirus Type 6 for Cancer Treatment.

• DOI: 10.3390/v15010182
• 发表时间: 2023-01-07
• 期刊: Viruses
• 作者: Osipov ID;Vasikhovskaia VA;Zabelina DS;Kutseikin SS;Grazhdantseva AA;Kochneva GV;Davydova J;Netesov SV;Romanenko MV
• 通讯作者: Romanenko MV