Novel Mechano-Acoustic Enhancement of Immunotherapy

免疫治疗的新型机械声增强

• 批准号: 10372815
• 负责人: Ahmed El Kaffas
• 金额: $ 18.47万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372815
• 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; Immunization; Immunohistochemistry; 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 Tissue; Work; anergy; anticancer activity; base; cancer therapy; cellular transduction; checkpoint therapy; clinically relevant; design; experimental study; immune activation; immunogenicity; immunoregulation; improved; in vivo; individualized medicine; 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 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

项目总结/摘要 尽管免疫疗法在治疗癌症方面具有前所未有的效果，但超过50-80%的患者不会接受免疫疗法。 对治疗有反应，并将忍受治疗引起的严重不良和危及生命的事件。方法 使肿瘤对免疫疗法敏感的方法正在迫切地探索中。一个非常有前途的方法是使用 由于已知的免疫调节作用而进行放射治疗。另一种有希望的方法是靶向肿瘤 内皮细胞与药物接触，以使其免疫抑制特性最小化。在正常组织中， 内皮细胞作为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。这超出了药物靶向 使治疗局部化并使全身效应或不良事件最小化。我们之前的研究 表明超声刺激的微泡（USMB）可以激活机械转导通路， 肿瘤内皮细胞通过机械声力，这反过来又显着提高放疗。 已知内皮免疫原性直接受机械力影响， 是一种已知的免疫调节剂，我们证实USMB治疗可以增强免疫调节作用， 可能包括辐射的策略。我们计划的研究包括：i）肿瘤内皮的表征 由机械力引起的免疫原性，和ii）联合治疗的临床前评估 治疗方案包括USMB、免疫疗法和/或放射。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，以及机械力是否可以改变 内皮表面标志物表达和一般免疫原性。有了这项研究，我们的目标将是 将启动一个更大的研究计划，旨在引入机械声力的免疫调节 在癌症和其他免疫性疾病中的作用，并在更先进和临床上研究这些作用- 相关的生物模型。 一年来另外作为