A Novel Oncolytic HSP Vaccine for Systemic Tumor Therapy

描述（由申请人提供）：溶瘤病毒已显示出抗肿瘤治疗的前景，但其作用仅限于局部肿瘤。肿瘤疫苗是一种有吸引力的治疗方法，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，肿瘤细胞通常不能刺激免疫反应，可能是由于抗原呈递不足。热休克蛋白（HSPs）具有混杂的能力，可以作为肿瘤细胞抗原的伴侣并呈现广泛的抗原库，在诱导抗肿瘤免疫反应中发挥关键作用。本研究的目的是结合溶瘤病毒和热休克蛋白肿瘤疫苗的优势特点，开发一种局部溶瘤病毒疗法，诱导全身抗肿瘤反应。我们假设可以产生一种表达热休克蛋白的重组溶瘤病毒，称为“溶瘤热休克蛋白疫苗”，并将具有双重功能：对局部肿瘤的溶瘤活性，随后释放肿瘤抗原，以及热休克蛋白介导的对转移性肿瘤的有效抗肿瘤反应。在我们的初步研究中，产生了一种表达hsp70的重组溶瘤腺病毒（Ad），并证明其对多种肿瘤细胞保持溶瘤活性，肿瘤内注射溶瘤HSP病毒可诱导全身抗肿瘤反应。本建议的具体目的是：1)。在能够支持人腺病毒感染的小鼠肿瘤模型中，验证Ad-I{E局部治疗可诱导全身抗肿瘤免疫反应的假设。2）. 目的：探讨Ad-HE治疗后HSP表达的增强是否促进DC肿瘤浸润和抗原提呈，以及浸润DC的哪些亚型肿瘤对诱导抗肿瘤免疫应答至关重要。3）. 为了验证用共表达SOCS1-siRNA的Ad-HE疫苗进行肿瘤内免疫可以通过持续激活促炎STAT和NF-？受感染的、socs1沉默的肿瘤浸润性dc和其他免疫细胞中的B信号我们提出的溶瘤热休克蛋白疫苗策略利用了溶瘤病毒和基于热休克蛋白的免疫疗法的优势，在一次治疗中可以根除局部和播散性肿瘤细胞，并可能普遍适用于广泛的恶性实体肿瘤。

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.