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，可以诱导特异性抗肿瘤免疫。然而，肿瘤细胞通常不能刺激免疫应答，可能是由于抗原呈递不足。热休克蛋白（HSPs）具有广泛的分子伴侣和肿瘤细胞抗原库的能力，在诱导抗肿瘤免疫应答中起着关键作用。本研究的目的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的肿瘤疫苗的优点，可以诱导全身性抗肿瘤反应。我们假设，表达HSP的重组溶瘤病毒，称为“溶瘤HSP疫苗”，可以产生并将具有双重功能：对局部肿瘤的溶瘤活性，随后释放肿瘤抗原，和有效的HSP介导的抗肿瘤反应，对转移性肿瘤。在我们的初步研究中，表达HSP 7 O的重组溶瘤腺病毒（Ad）产生并证明保留对各种肿瘤细胞的溶瘤活性，并且瘤内注射溶瘤HSP病毒诱导全身性抗肿瘤反应。这项建议的具体目标是：1）。为了检验在能够支持人腺病毒感染的鼠肿瘤模型中通过用Ad-I β E局部治疗诱导全身性抗肿瘤免疫应答的假设。2）。为了确定Ad-HE处理增强的HSP表达是否促进DC肿瘤浸润和抗原呈递，以及肿瘤浸润DC的哪些亚型对诱导抗肿瘤免疫应答至关重要。3）。为了验证以下假设，即用共表达SOCS 1-siRNA的Ad-HE疫苗进行瘤内免疫将通过持续激活促炎性STAT和NF-？受感染的SOCS 1沉默的肿瘤浸润DC和其他免疫细胞中的B信号传导。我们提出的溶瘤HSP疫苗策略利用溶瘤病毒和基于HSP的免疫疗法的优点，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谱的恶性实体瘤。

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.