A Novel Oncolytic HSP Vaccine for Systemic Tumor Therapy

描述(申请人提供)：溶瘤病毒已显示出作为抗肿瘤治疗的前景，但它们的效果仅限于局部肿瘤。肿瘤疫苗是一种有吸引力的治疗方法，因为肿瘤细胞含有大量的基因突变，可以诱导特异性的抗肿瘤免疫。然而，肿瘤细胞通常无法刺激免疫反应，这可能是由于抗原提呈不足所致。热休克蛋白(HSPs)具有杂乱的伴侣能力和广泛的肿瘤细胞抗原库，在诱导抗肿瘤免疫反应中起着关键作用。本研究的目的是结合溶瘤病毒和基于HSP的肿瘤疫苗的优点，开发一种能够诱导全身抗肿瘤反应的局部溶瘤病毒疗法。我们推测，一种表达HSP的重组溶瘤病毒，被称为“溶瘤HSP疫苗”，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，以及强大的HSP介导的抗肿瘤转移反应。在我们的初步研究中，我们构建了表达HSP7O的重组溶瘤腺病毒(Ad)，并证明其对多种肿瘤细胞具有溶瘤活性，瘤内注射溶瘤HSP病毒可诱导全身抗肿瘤反应。这项建议的具体目的是：1)。目的：在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说。2)。为了确定Ad-HE治疗后HSP表达增强是否促进了DC肿瘤的侵袭和抗原提呈，以及哪些肿瘤浸润性DC亚型在诱导抗肿瘤免疫反应中起关键作用。3)。为了验证共表达SOCS1-siRNA的Ad-HE疫苗瘤内免疫可通过持续激活感染的、SOCS1沉默的肿瘤浸润性DC和其他免疫细胞中的促炎状态和核因子？B信号来克服肿瘤介导的免疫抑制的假说。我们提出的溶瘤HSP疫苗策略利用了溶瘤病毒和基于HSP的免疫治疗的优势，在单一治疗中可以根除局部和播散的肿瘤细胞，并可能普遍适用于广泛的恶性实体瘤。

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.