Breast cancer virotherapy

乳腺癌病毒治疗

• 批准号: 10358606
• 负责人: BIN HE
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358606
• 关键词: Antitumor Response; Australia; Biological; Breast Cancer Model; Breast Cancer therapy; Cancer Etiology; Cell Death; Cell Maturation; Cell Proliferation; Cells; Cessation of life; Clinical; Combination immunotherapy; Combined Modality Therapy; Coupled; Dendritic Cells; Development; Disease; Distant; Early Diagnosis; Early treatment; Engineering; Epigenetic Process; Europe; FDA approved; Genes; Genetic; Genetic Engineering; Genome; Goals; Herpes Simplex Infections; Herpesviridae; Herpesvirus 1; Human; Immune; Immune Targeting; Immune response; Immune system; Immunologics; Immunosuppression; Individual; Inflammation; Inflammatory; Interferons; Knock-out; Lobular; Malignant Neoplasms; Mammary Duct; Mammary Neoplasms; Mediating; Metastatic to; Mutation; N-terminal; Natural Immunity; Nature; Normal Cell; Normal tissue morphology; Oncogenes; Oncolytic; Oncolytic Immunotherapy; Oncolytic viruses; Pathway interactions; Patients; Periodicity; Pre-Clinical Model; Process; Production; Recombinants; Recurrence; Refractory; Research; Second Messenger Systems; Signal Transduction; Stimulator of Interferon Genes; Survival Rate; Switzerland; Technology; Therapeutic; Treatment Efficacy; Tumor Antigens; Tumor Immunity; Tumor Suppressor Genes; Vertebral column; Virus; Virus Replication; Woman; Work; anti-PD1 antibodies; anti-cancer; cancer cell; cancer diagnosis; cancer therapy; chemokine; cytokine; design; gene product; immune checkpoint blockade; immunogenic; improved; in vivo; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; novel; oncolytic herpes simplex virus; oncolytic virotherapy; orthotopic breast cancer; pre-clinical; standard care; synergism; therapeutically effective; tumor; tumor microenvironment

Breast cancer is the most frequently diagnosed cancer in women worldwide. Despite advances in early detection and treatment, a notable fraction of patients progress to metastatic disease where no cure exists. Accordingly, there is a pressing need for effective therapeutic strategies. Breast cancer arises primarily due to genetic or epigenetic alterations that aberrantly regulate oncogenes, tumor-suppressor genes or immune genes. While advantageous for cancer cell proliferation or immune-escape, these changes often make malignant cells vulnerable to attack by oncolytic herpes simplex (HSV). There is now increased recognition that dynamic virus-host interplay determines the magnitude of cell destruction or release of immunogenic factors. Preliminary studies suggest that recombinant HSV that lacks selected gene motifs efficiently replicates in and lyses cancer cells. Furthermore, it activates dendritic cells that are necessary to mediate adaptive antitumor immunity. We hypothesize that selectively engineered HSV may serve as a distinct anticancer platform, which destructs malignant cells meanwhile primes superior antitumor immunity. With state of the art technology, we will determine the therapeutic potency of oncolytic HSV in preclinical models. As such, we will systematically examine the antitumor activities exerted by genetically modified HSV. To achieve therapeutic synergy, we will integrate cyclic GAMP synthase, a key factor of innate immunity, into the oncolytic virus backbone. In addition, we will characterize its oncolytic efficacy in combination with an immune checkpoint blockade. Lastly, we will investigate the nature by which oncolytic HSV remodels the tumor microenvironment for antitumor responses. Collectively, these studies may facilitate the development of novel agents for breast cancer therapy.

乳腺癌是全世界女性最常被诊断出的癌症。 尽管在早期发现和治疗方面取得了进展，但仍有相当一部分患者取得了进展 到无法治愈的转移性疾病。因此，迫切需要 有效的治疗策略。乳腺癌的发生主要是由于遗传或表观遗传。 异常调节癌基因、肿瘤抑制基因或免疫基因的变化。 虽然这些变化有利于癌细胞的增殖或免疫逃逸，但通常 使恶性细胞容易受到溶瘤单纯疱疹病毒(HSV)的攻击。的确有 现在越来越多的人认识到，动态的病毒与宿主的相互作用决定了 细胞破坏或免疫原因子的释放。初步研究表明， 缺乏选择基因基序的重组HSV有效地复制和裂解 癌细胞。此外，它还激活树突状细胞，这是介导 适应性抗肿瘤免疫。我们假设选择性设计的单纯疱疹病毒可能 作为一个独特的抗癌平台，同时摧毁恶性细胞 具有卓越的抗肿瘤免疫力。凭借最先进的技术，我们将确定 临床前模型中溶瘤单纯疱疹病毒的治疗效果。因此，我们将 系统检测转基因单纯疱疹病毒的抗肿瘤活性。至 实现治疗的协同效应，我们将整合环磷酸腺苷合成酶，一个关键的因素 先天免疫，进入溶瘤病毒主干。此外，我们还将描述其特性 与免疫检查点阻断相结合的溶瘤效果。最后，我们将 探讨溶瘤单纯疱疹病毒改变肿瘤微环境的本质 抗肿瘤反应。总而言之，这些研究可能有助于小说的发展 乳腺癌治疗药物。