Strategies to Enhance Virotherapy for Breast Cancer

描述（由申请人提供）：溶瘤病毒代表了治疗恶性疾病（如乳腺癌）的一种有价值的新模式，因为它们可以选择性地在肿瘤细胞中复制，同时保留正常细胞。与典型的基于基因的癌症治疗形式不同，溶瘤病毒通过其选择性复制/细胞溶解并随后扩散到周围肿瘤组织来直接杀死肿瘤细胞。这些性质提供了一个主要的优势，基因传递的固有效率低下，因此有限的肿瘤细胞杀伤往往与基因介导的治疗。在上一个资助期间进行的工作表明，将细胞膜融合活性掺入溶瘤性单纯疱疹病毒（HSV）中可以显着增强该病毒对乳腺癌的肿瘤杀伤作用。此外，通过双融合溶瘤HSV（Synco-2D）的肿瘤破坏可以引发有效的抗肿瘤免疫应答。目前的提案建立在这些先前的进展基础上，并研究了可以最大限度地发挥Synco-2D抗肿瘤作用的策略，从而增加了其临床成功的可能性。我们提出的研究的目的1将检查Synco-2D的抗肿瘤活性是否可以通过合理设计的组合策略进一步增强，包括将血栓形成诱导因子掺入病毒和改变肿瘤微环境以有利于病毒复制。目的2将探索可以改善由Synco-2D介导的溶瘤引起的抗肿瘤免疫应答的功能的策略。特别是，我们将研究共刺激分子的表观遗传上调是否可以显着改善诱导的抗肿瘤免疫的功能。我们还将确定酸性肿瘤微环境是否影响免疫效应细胞的抗肿瘤活性，并探索可以逆转不良反应的策略。目标3将寻求开发策略，使Synco-2D能够破坏肿瘤干细胞，以获得持久的治疗效果。该项目的长期目标是开发一种有效的病毒疗法，能够对晚期乳腺癌产生显著的治疗效果，并有可能在不久的将来转化为临床应用。 公共卫生相关性：尽管最近在早期诊断和治疗方面取得了进展，但乳腺癌患者的预后仍然很差。该提案旨在开发一种新的病毒疗法来治疗晚期乳腺癌患者，拟议研究的成功将极大地造福于患有这种恶性疾病的患者。

DESCRIPTION (provided by applicant): Oncolytic viruses represent a valuable new modality for the treatment of malignant diseases such as breast cancer, as they can selectively replicate in tumor cells while sparing normal cells. Unlike typical gene-based forms of cancer therapy, oncolytic viruses kill tumor cells directly through their selective replication/cytolysis and consequent spread to surrounding tumor tissues. These properties offer a major advantage over the inherent inefficiency of gene delivery and thus the limited tumor cell killing often seen with gene-mediated therapy. Work conducted during the previous funding period has demonstrated that incorporation of cell membrane fusion activity into an oncolytic herpes simplex virus (HSV) can significantly enhance the tumor killing effect of the virus against breast cancer. Moreover, tumor destruction by a doubly fusogenic oncolytic HSV (Synco-2D) can elicit effective antitumor immune responses. The current proposal builds upon these prior advances and investigates strategies that can maximize the antitumor effect of Synco-2D, thus increasing the likelihood of its clinical success. The Aim 1 of our proposed studies will examine if the antitumor activity of Synco-2D can be further enhanced by rationally designed combinatorial strategies, including incorporation of a thrombosis-inducing factor into the virus and alteration of tumor microenvironment to favor the virus replication. Aim 2 will explore strategies that can improve the functionality of antitumor immune responses elicited by Synco-2D-mediated oncolysis. In particular, we will investigate if epigenetic upregulation of costimulatory molecules can significantly improve the functionality of the induced antitumor immunity. We will also determine if the acidic tumor microenvironment affects the antitumor activity of immune effector cells, and explore strategies that can reverse the adverse effect. Aim 3 will seek to develop strategies that enable Synco-2D to destroy tumor stem cells for a long-lasting therapeutic effect. The long-term goal of this project is to develop a potent virotherapy capable of producing significant therapeutic effects against advanced-stage breast cancer, with the potential to be translated into clinical use in the near future. PUBLIC HEALTH RELEVANCE: Despite recent progresses in early diagnosis and treatment, patients with breast cancer still have very poor prognoses. This proposal seeks to develop a novel virotherapy to treat patients with late stage breast cancer and success of the proposed studies will greatly benefit patients suffering from this malignant disease.