Novel Mechano-Acoustic Enhancement of Immunotherapy

免疫治疗的新型机械声增强

基本信息

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
项目类别：
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

项目摘要

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

项目概要/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，并会因治疗方法而承受严重的不良和危及生命的事件。目前正在迫切探索一种使肿瘤对免疫疗法敏感的方法。由于已知的免疫调节作用而进行的放射治疗是针对肿瘤的另一种有前途的方法。内皮细胞与药物，以尽量减少其免疫抑制特性在正常组织中，内皮细胞充当免疫系统的调节门户，在癌症中，内皮细胞具有高度的功能。我们建议探索增强肿瘤的新方法。通过机械靶向肿瘤内皮细胞来产生免疫原性，这超出了药物靶向的范围。局部治疗并最大程度地减少系统性影响或不良事件。证明超声刺激微泡（USMB）可以激活机械传导通路通过机械声力作用肿瘤内皮细胞，从而显着增强放射治疗。鉴于已知内皮免疫原性直接受到机械力的影响，并且辐射是一种已知的免疫调节剂，我们认为 USMB 治疗可以增强免疫治疗的效果我们提出的研究可能包括：i) 肿瘤内皮的表征。机械力引起的免疫原性，以及 ii) 联合治疗的临床前评估通过这项工作，我们还将获得更深入的治疗方案，包括 USMB、免疫治疗和/或放射治疗。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借助这项研究，我们的目标将是内皮表面标志物表达和一般免疫原性。启动一项更大的研究计划，旨在引入机械声学力进行免疫调节在癌症和其他基于免疫的疾病中，并在更先进的临床研究中研究这些影响相关的生物学模型。过去的一年。