Cancer therapy with a combination of oncolytic bacteria and virus to enhance targeted cell killing and anti-tumor immune responses

结合溶瘤细菌和病毒进行癌症治疗，增强靶向细胞杀伤和抗肿瘤免疫反应

• 批准号: 10319008
• 负责人: Wei Kong
• 金额: $ 17.98万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319008
• 关键词: Affect; Aftercare; Antibodies; Antigen-Antibody Complex; Antineoplastic Agents; Apoptosis; Bacteria; Beds; Binding; Cancer Model; Cancer Patient; Cause of Death; Cells; Cellular Stress; Chemotaxis; Clinic; Colon Carcinoma; Colorectal Cancer; DNA Viruses; Dendritic Cells; Exhibits; Family; Flagellin; Genetic; Genetic Engineering; Goals; Immune; Immune checkpoint inhibitor; Immune system; Immunoglobulin G; Immunologics; Individual; Interferon Type II; Interferons; Interleukin-12; Invaded; Leukocytes; Ligands; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metastatic Neoplasm to the Liver; Microbe; Mus; Myxoma virus; Natural Killer Cells; Necrosis; Neoplasm Metastasis; Oncolytic; Oncolytic viruses; PTPRC gene; Patients; Process; Property; Research; Salmonella; Salmonella typhimurium; Shapes; Societies; Stimulus; Stress; System; TNF gene; Testing; Therapeutic; Time; Transgenes; United States; Virus; XCL1 gene; adaptive immune response; anti-tumor immune response; base; cancer cell; cancer immunotherapeutics; cancer immunotherapy; cancer therapy; cancer type; cell killing; chemokine; chimeric antigen receptor T cells; cytokine; decorin; design and construction; exhaust; immune activation; improved; lung small cell carcinoma; microbial; mouse model; neoplastic cell; novel; novel therapeutics; pathogen; pre-clinical; recruit; response; success; survival outcome; therapy outcome; tumor

Project Summary/Abstract Cancer is one of the leading causes of death in the United States and worldwide. Appropriate activation of the immune system and effective targeting of tumor cells are the primary hurdles to be overcome for successful cancer immunotherapy. Microbes-based therapy was extensively studied recently to fill the critical unmet needs of cancer patients, where the current treatment options have been exhausted. We have developed genetically engineered Salmonella (GMS), which can actively search for cancer cells, induce tumor regression, prolong survival time, and inhibit cancer metastasis in multiple mouse models. They can also eradicate themselves from the host after treatment. Interestingly, Salmonella also processes multiple natural killer (NK) cell stimulators. On the other hand, oncolytic viruses are new cancer immunotherapeutics and have been approved to use in the clinic. Oncolytic Myxoma virus (MYXV) has been tested in multiple preclinical cancer models and has demonstrated immune stimulating properties for cancer treatment. MYXV was able to bring CD45+ leukocytes to the tumor bed. In addition, these large DNA viruses can be armed to express additional immune activating molecules. In this study, we propose to explore a novel cancer treatment approach that combines the targeted cancer cell killing ability of bacteria and immune stimulating abilities of both oncolytic bacteria and viruses. Apart from the direct killing of cancer cells, improved GMS will stimulate NK cells and MYXV will recruit other tumor-infiltrating leukocytes to activate the anti-tumor immune responses. In addition, we will explore the transgene expressing armed MYXVs that will express cytokines and chemokines to recruit more specific tumor-infiltrating leukocytes. The success of our efforts would turn microbes to appropriate onsite attractors and activators of the immune system for effective cancer therapy to be successful and applicable across a wide range of tumor types.

项目总结/摘要 癌症是美国和全世界的主要死亡原因之一。适当激活 免疫系统和肿瘤细胞的有效靶向是成功治疗癌症需要克服的主要障碍。 癌症免疫疗法基于微生物的治疗最近被广泛研究，以填补关键的未满足的 癌症患者的需求，目前的治疗方案已经用尽。我们已经开发 基因工程沙门氏菌（GMS），它可以积极寻找癌细胞，诱导肿瘤消退， 在多种小鼠模型中延长存活时间并抑制癌症转移。他们也可以根除 治疗后的主人。有趣的是，沙门氏菌还处理多种自然杀伤细胞（NK） 细胞刺激剂另一方面，溶瘤病毒是新的癌症免疫治疗剂， 允许在诊所使用。溶瘤粘液瘤病毒（MYXV）已在多种临床前癌症中进行了测试 模型，并已证明用于癌症治疗的免疫刺激特性。MYXV能够带来 CD 45+白细胞转移到肿瘤床。此外，这些大的DNA病毒可以武装起来表达额外的DNA。 免疫激活分子在这项研究中，我们建议探索一种新的癌症治疗方法， 结合了细菌的靶向癌细胞杀伤能力和溶瘤药物的免疫刺激能力， 细菌和病毒。除了直接杀死癌细胞外，改良的GMS还将刺激NK细胞， MYXV将招募其他肿瘤浸润白细胞来激活抗肿瘤免疫反应。此外，本发明还提供了一种方法， 我们将探索转基因表达的武装MYXV，它将表达细胞因子和趋化因子， 更特异的肿瘤浸润性白细胞我们努力的成功将使微生物在适当的场所 免疫系统的吸引剂和激活剂用于有效的癌症治疗是成功的和适用的 广泛的肿瘤类型。