A Novel Oncolytic HSP Vaccine for Systemic Tumor Therapy

用于全身肿瘤治疗的新型溶瘤热休克蛋白疫苗

基本信息

批准号：
7163572
负责人：
XUE F HUANG
金额：
$ 20.68万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-27 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7163572
关键词：
5,5&apos ,6,6&apos -tetrachloro-1,1&apos ,3,3&apos -tetraethylbenzimidazolocarbocyanine Adenoviruses Antigen Presentation Antigens Antitumor Response Cancer Vaccines Cells Complex Cytokine Inducible SH2-Containing Protein Dendritic Cells Development Distant Feedback Gene Mutation Goals Heat shock proteins Heat-Shock Proteins 70 Human Adenovirus Infections Immune Immune response Immunity Immunization Immunosuppression Immunotherapy Infiltration Injection of therapeutic agent Local Therapy Malignant - descriptor Mediating Modeling Molecular Chaperones Mus NF-kappa B Neoplasm Metastasis Numbers Oncolytic Oncolytic viruses Pathway interactions Peptides Play Principal Investigator Protein Overexpression Recombinants Role Signal Pathway Signal Transduction Small Interfering RNA Solid Neoplasm T-Lymphocyte Testing Therapeutic immunosuppression Tumor Antigens Tumor Subtype Vaccines Viral Virus base chemokine cytotoxicity in vivo killings macrophage neoplastic cell novel programs protein expression tumor

项目摘要

DESCRIPTION (provided by applicant): Oncolytic viruses have shown promise as antitumor therapy, but their effects have been limited to local tumors. Tumor vaccines are attractive therapy because tumor cells harbor numerous genetic mutations that could induce specific antitumor immunity. Yet, tumor cells are generally incapable of stimulating an immune response, probably due to inadequate antigen presentation. Heat-shock proteins (HSPs) with the promiscuous ability to chaperone and present a broad repertoire of tumor cell antigens play a critical role in the induction of antitumor immune responses. The goal of this study is to develop a local oncolytic virus therapy that can induce systemic antitumor responses by combining the advantageous features of oncolytic viruses and HSP-based tumor vaccines. We hypothesize that a recombinant oncolytic virus expressing HSP, referred to as "oncolytic HSP vaccine", can be generated and will possess dual functions: oncolytic activity against local tumor followed by the release of tumor antigens, and potent HSP-mediated antitumor responses against metastatic tumors. In our preliminary study, a recombinant oncolytic adenovirus (Ad) expressing HSP7O was generated and demonstrated to retain oncolytic activity against various tumor cells, and intratumor injection of the oncolytic HSP virus induced systemic antitumor responses. The specific aims of this proposal are: 1). To test the hypothesis that systemic antitumor immune responses are induced by local therapy with Ad-I{E in murine tumor models capable of supporting human adenovirus infection. 2). To determine whether that enhanced HSP expression by Ad-HE treatment promotes DC tumor infiltration and antigen presentation and which subtypes of tumor infiltrating DCs are critical to induce antitumor immune responses. 3). To test the hypothesis that intratumor immunization with Ad-HE vaccine coexpressing SOCS1-siRNA will overcome tumor-mediated immunosuppression by persistent activation of proinflammatory STAT and NF-?B signaling in infected, SOCS1-silenced tumor-infiltrating DCs and other immune cells. The oncolytic HSP vaccine strategy we propose exploits the advantageous features of oncolytic viruses and HSP-based immunotherapy in a single treatment that may eradicate both local and disseminated tumor cells and may be universally applicable to a broad spectrum of malignant solid tumors.

描述（由申请人提供）：溶瘤病毒已显示出作为抗肿瘤治疗的前景，但其作用仅限于局部肿瘤。肿瘤疫苗是一种有吸引力的疗法，因为肿瘤细胞含有许多基因突变，可以诱导特异性抗肿瘤免疫。然而，肿瘤细胞通常无法刺激免疫反应，可能是由于抗原呈递不足。热休克蛋白（HSP）具有混杂的伴侣能力并呈递广泛的肿瘤细胞抗原，在诱导抗肿瘤免疫反应中发挥着关键作用。本研究的目标是开发一种局部溶瘤病毒疗法，通过结合溶瘤病毒和基于 HSP 的肿瘤疫苗的优势特征，可以诱导全身抗肿瘤反应。我们假设可以产生表达 HSP 的重组溶瘤病毒，称为“溶瘤 HSP 疫苗”，并将具有双重功能：针对局部肿瘤的溶瘤活性，随后释放肿瘤抗原，以及针对转移性肿瘤的有效 HSP 介导的抗肿瘤反应。肿瘤。在我们的初步研究中，产生了表达HSP7O的重组溶瘤腺病毒（Ad），并证明其保留了针对各种肿瘤细胞的溶瘤活性，并且溶瘤HSP病毒的肿瘤内注射诱导了全身抗肿瘤反应。该提案的具体目标是：1）。检验这样的假设：在能够支持人腺病毒感染的小鼠肿瘤模型中，Ad-I{E 局部治疗可诱导全身抗肿瘤免疫反应。 2）。旨在确定 Ad-HE 治疗增强的 HSP 表达是否促进 DC 肿瘤浸润和抗原呈递，以及肿瘤浸润 DC 的哪些亚型对于诱导抗肿瘤免疫反应至关重要。 3）。测试以下假设：使用共表达 SOCS1-siRNA 的 Ad-HE 疫苗进行肿瘤内免疫将通过在受感染、SOCS1 沉默的肿瘤浸润 DC 和其他免疫细胞中持续激活促炎 STAT 和 NF-κB 信号来克服肿瘤介导的免疫抑制。我们提出的溶瘤HSP疫苗策略利用了溶瘤病毒和基于HSP的免疫疗法的优势特征，在单一治疗中可以根除局部和播散性肿瘤细胞，并且可以普遍适用于广泛的恶性实体瘤。