TRANSFECTANT INFLUENZA VIRUSES IN CANCER THERAPY

转染流感病毒在癌症治疗中的应用

• 批准号: 2592794
• 负责人: Adolfo Garcia-Sastre
• 金额: $ 13.73万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2592794
• 关键词: antineoplastics; beta galactosidase; biomaterial development /preparation; cellular immunity; cytotoxic T lymphocyte; disease /disorder model; drug screening /evaluation; gene expression; genetic manipulation; genetic regulatory element; immune tolerance /unresponsiveness; immunization; influenzavirus A; laboratory mouse; melanoma; neoplasm /cancer therapy; nonhuman therapy evaluation; recombinant virus; tissue /cell culture; transfection /expression vector; tumor antigens

DESCRIPTION: (Applicant's Abstract) Recently, different tumor associated antigens (TAAs) which are capable of being recognized by tumor infiltrating lymphocytes have been identified. The success of cancer therapies may depend on the induction of effective cellular immune responses against TAAs. A very promising approach to treat tumors involves the use of recombinant viral vectors expressing the desired TAAs, since most viruses are able to elicit strong and long-lasting immune responses against their expressed antigens. Earlier it was shown that transfectant influenza virus vectors could induce powerful cellular immune responses against the expressed antigens in mice, especially when they were administered in combination with recombinant vaccinia viruses expressing the same antigen. In this application, the antitumor immune responses elicited by transfectant influenza viruses expressing a model TAA will be analyzed in mice. Novel protocols of immunization, including the use of two different viral vectors to induce powerful antitumor cellular immune responses, will be studied. In addition, experiments focused on improving the safety of the transfectant influenza viruses have also been designed. The influence of cis-acting RNA sequences in the regulation of influenza virus gene expression, in viral pathogenicity, and immunogenicity will be determined. Stably attenuated transfectant influenza viruses expressing a model murine TAA will be engineered and their antitumor properties will be characterized. Finally, influenza virus vectors expressing human tumor associated antigens from melanoma tumors will be constructed for possible future use in humans. The ability of cells which have been infected with these viruses to be recognized by tumor infiltrating lymphocytes will be analyzed. The proposed research may advance the field of cancer therapy towards possible novel ways to treat human tumors and prolong survival of cancer patients.

描述：（申请人的摘要）最近，不同的肿瘤相关的 能够被肿瘤浸润识别的抗原（TAA） 淋巴细胞已被鉴定。 癌症治疗的成功可能 依赖于诱导针对TAA的有效细胞免疫应答。 一种非常有前途的治疗肿瘤的方法涉及使用重组的 表达所需TAA的病毒载体，因为大多数病毒能够 引发针对其表达的强而持久的免疫应答， 抗原 早期研究表明，转染流感病毒载体 可以诱导强大的细胞免疫反应， 抗原，特别是当它们与 表达相同抗原的重组牛痘病毒。 在这 应用中，转染子引起的抗肿瘤免疫应答 将在小鼠中分析表达模型TAA的流感病毒。 小说 免疫方案，包括使用两种不同的病毒载体 以诱导强大的抗肿瘤细胞免疫应答。 在 此外，实验集中于提高转染子的安全性， 流感病毒也被设计出来。 顺式作用RNA的影响 流感病毒基因表达调控中的序列， 致病性和免疫原性。 稳定衰减 表达模型鼠TAA的转染流感病毒将 工程化，并将表征其抗肿瘤特性。 最后， 表达人肿瘤相关抗原的流感病毒载体 将构建黑色素瘤肿瘤，以备将来用于人类。 的 被这些病毒感染的细胞， 将分析由肿瘤浸润淋巴细胞识别的细胞。 拟议 研究可能会推动癌症治疗领域朝着可能的新方法发展， 来治疗人类肿瘤并延长癌症患者的生存期。