Novel Mechano-Acoustic Enhancement of Immunotherapy

免疫治疗的新型机械声增强

• 批准号: 10544783
• 负责人: Ahmed El Kaffas
• 金额: $ 21.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544783
• 关键词: Ablation; Acoustics; Acute; Adverse event; Affect; Area; Biological Models; Biology; Blood Vessels; Cancer Patient; Cell Adhesion Molecules; Cell Death; Cell surface; Cells; Characteristics; Clinical; Combined Modality Therapy; Contrast Media; Disease; Endothelial Cells; Endothelium; Event; FDA approved; Flow Cytometry; Goals; Hour; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunohistochemistry; Immunologic Sensitization; Immunomodulators; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Infiltration; Inflammation; Intercellular adhesion molecule 1; Life; Link; Liver neoplasms; Malignant Neoplasms; Mechanics; Mediating; Microbubbles; Mutation; Nature; Normal tissue morphology; Oncologist; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Property; Radiation; Radiation therapy; Research; Role; Sonication; Surface; Testing; Therapeutic; Tissues; Treatment Protocols; Tumor Cell Line; Tumor Tissue; Work; anergy; anticancer activity; cancer therapy; cellular transduction; checkpoint therapy; clinically relevant; design; experimental study; immune activation; immune cell infiltrate; immunogenicity; immunoregulation; improved; in vivo; individualized medicine; inhibitor therapy; mechanical force; mechanotransduction; novel; novel strategies; pre-clinical assessment; programmed cell death ligand 1; programs; radiation effect; success; treatment effect; treatment response; treatment strategy; tumor; tumor ablation; tumor growth; ultrasound

PROJECT SUMMARY/ABSTRACT Despite the unprecedented effects of immunotherapy in treating cancer, over 50–80% of patients will not respond to treatment and will endure severe adverse and life-threatening events due to treatment. Approaches to sensitize tumors to immunotherapy are urgently being explored. One very promising approach is the use of radiation therapy due to known immunomodulating effects. Another promising approach is to target tumor endothelial cells with pharmaceuticals to minimize their immunosuppressive properties. In normal tissues, endothelial cells act as a regulating gateway for the immune system. In cancer, endothelial cells are highly abnormal and immunosuppressive. We propose to explore novel approaches to enhance tumor immunogenicity by mechanical targeting of tumor endothelial cells. This goes beyond pharmaceutical targeting localizing the treatment and minimizing systemic effects or adverse events. Our previous research demonstrated that ultrasound-stimulated microbubbles (USMB) can activate mechanotransduction pathways in tumor endothelial cells through mechano-acoustic forces, which in turn significantly enhance radiotherapy. Given that endothelial immunogenicity is known to be directly affected by mechanical forces, and that radiation is a known immunomodulator, we posit that USMB treatments can enhance the effects of immunotherapeutic strategies that may include radiation. Our proposed research includes: i) characterization of tumor endothelium immunogenicity resulting from mechanical forces, and ii) pre-clinical assessment of combined treatment regimens that include USMB, immunotherapy and/or radiation. Through this work, we will also gain a deeper understanding of the role of endothelial cells in immunotherapy, and whether mechanical forces can alter endothelial surface marker expression and general immunogenicity. Equipped with this research, our goal will be to initiate a larger research program designed to introduce mechano-acoustic forces for immunomodulation in cancer and in other immune-based diseases, and to study these effects in more advanced and clinically- relevant biological models. past year. In addition, as

项目摘要/摘要 尽管免疫疗法在治疗癌症方面取得了前所未有的效果，但超过50%-80%的患者不会 对治疗有反应，并将忍受由于治疗而产生的严重不良反应和危及生命的事件。方法 使肿瘤对免疫治疗敏感的方法正在迫切地探索中。一种非常有希望的方法是使用 放射治疗由于已知的免疫调节作用。另一种有希望的方法是靶向肿瘤。 血管内皮细胞使用药物将其免疫抑制性能降至最低。在正常组织中， 内皮细胞是免疫系统的调节通道。在癌症中，内皮细胞高度 异常和免疫抑制。我们建议探索新的方法来增强肿瘤 通过机械靶向肿瘤内皮细胞的免疫原性。这超越了药物靶向 使治疗局部化，将全身影响或不良事件降至最低。我们之前的研究 超声刺激的微泡(USMB)可激活机械信号转导通路 肿瘤内皮细胞通过机械-声学作用力，进而显著增强放射治疗。 鉴于已知内皮细胞的免疫原性直接受到机械力的影响，而且辐射 是一种已知的免疫调节剂，我们假设USMB治疗可以增强免疫治疗的效果 可能包括辐射在内的策略。我们提出的研究包括：i)肿瘤内皮的特征 机械力引起的免疫原性，以及ii)联合治疗的临床前评估 治疗方案包括USMB、免疫治疗和/或放射治疗。通过这项工作，我们也将获得更深层次的 了解内皮细胞在免疫治疗中的作用，以及机械力是否会改变 内皮细胞表面标志物的表达和一般免疫原性。有了这项研究，我们的目标将是 将启动一项更大的研究计划，旨在为免疫调节引入机械声学力量 在癌症和其他基于免疫的疾病中，并在更先进的临床上研究这些影响- 相关的生物学模型。 过去的一年。此外，AS