Breast cancer virotherapy

乳腺癌病毒治疗

基本信息

批准号：
10197539
负责人：
BIN HE
金额：
$ 18.69万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197539
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

项目摘要

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.

乳腺癌是全球女性最常被诊断出的癌症。尽管早期检测和治疗方面取得了进步，但很明显的患者进展对于不存在治愈的转移性疾病。因此，有紧迫的需求有效的治疗策略。乳腺癌主要是由于遗传或表观遗传学而引起的异常调节肿瘤基因，肿瘤抑制基因或免疫基因的改变。虽然对癌细胞增殖或免疫灭绝有利，但这些变化经常使恶性细胞容易受到溶瘤疱疹（HSV）的攻击。有现在，人们对动态病毒宿主相互作用的认识提高了决定的大小免疫原性因子的细胞破坏或释放。初步研究表明缺乏选定基因基序的重组HSV有效地复制和裂解癌细胞。此外，它激活了介导的树突状细胞自适应抗肿瘤免疫。我们假设有选择性地设计的HSV可能充当独特的抗癌平台，这会破坏恶性细胞 Primes上级抗肿瘤免疫。使用最先进的技术，我们将确定临床前模型中溶瘤HSV的治疗效力。因此，我们会系统地检查了基因修饰的HSV发挥的抗肿瘤活性。到达到治疗性协同作用，我们将整合环状GAMP合酶，这是先天免疫，进入溶瘤病毒主链。此外，我们将描述它的结合免疫检查点封锁结合溶瘤功效。最后，我们会的调查溶瘤HSV对肿瘤微环境的重塑的性质抗肿瘤反应。总的来说，这些研究可以促进新颖的发展乳腺癌治疗的药物。