Harnessing the therapeutic potential of histotripsy focused ultrasound-induced immunogenic cancer cell death

利用组织解剖聚焦超声诱导免疫原性癌细胞死亡的治疗潜力

• 批准号: 10654919
• 负责人: Clifford Cho
• 金额: $ 42.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654919
• 关键词: Ablation; Abscopal effect; Antigen-Presenting Cells; Antigens; Attention; CD8-Positive T-Lymphocytes; Cancer and Suicide; Cell Communication; Cell Death; Cells; Cessation of life; Clinical; Colon Carcinoma; Data; Detection; Distant; Event; Focused Ultrasound; Focused Ultrasound Therapy; Foundations; Future; Heating; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Stimulation; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammation; Inflammatory; Intervention; Investigation; Ionizing radiation; Length; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mechanics; Mediating; Metabolic; Modality; Pathway interactions; Patients; Physiologic pulse; Process; Radiation; Role; Series; Signal Transduction; Site; T cell infiltration; T-Cell Depletion; Technology; Testing; Therapeutic; Thermal Ablation Therapy; Tissues; Translating; Tumor Antigens; Ultrasonic wave; Work; adaptive immune response; adaptive immunity; anti-tumor immune response; cancer cell; cancer immunotherapy; carcinogenesis; cell killing; cell suicide; checkpoint inhibition; clinical practice; clinically relevant; cytotoxicity; immunogenic; immunogenic cell death; immunogenicity; inhibitor; insight; melanoma; millimeter; mouse model; multidisciplinary; neoplastic cell; new technology; pre-clinical; preservation; traditional therapy; tumor; tumor ablation

PROJECT SUMMARY/ABSTRACT Immunotherapy can be highly effective against cancers that elicit some recognition from the immune system (e.g., melanoma), but it remains ineffectual against cancers that are largely invisible to immune detection (e.g., pancreatic cancer). Advances in cancer immunotherapy will require interventions that can make cancers more apparent to the immune system. A growing body of evidence suggests that focused ultrasound (FUS) tumor ablation could be that intervention. By non-invasively disrupting cancer cells, thermal and mechanical modes of FUS have been shown to trigger surprisingly potent immune responses against tumors. We have found that histotripsy, a non-thermal mode of mechanical FUS, stimulates a powerful and systemic anti-tumor immune response strong enough to cause abscopal regression of distant, non-ablated tumor sites – effects not generally seen with traditional therapies like radiation or thermal ablation. Histotripsy is a technology that is presently being introduced into clinical use; therefore, it will be imperative to understand the mechanistic underpinnings of histotripsy immunostimulation. Our preliminary studies point to a stepwise series of events that may explain this phenomenon. First, histotripsy causes the release of subcellular cancer cell antigens in a manner that preserves their immunogenic integrity. Second, histotripsy induces cancer cells to undergo a specific pathway of cellular suicide called necroptosis – a death pathway that attracts inflammation and immune attention, effectively priming the immune system to recognize cancer antigens. What follows is a progressive infiltration of CD8+ T cells into distant tumors that is accompanied by another pathway of cancer cell death called ferroptosis – a death pathway recently discovered to be the critical mechanism by which immunotherapy-primed CD8+ T cells kill cancer cells. In this proposal, we will retrace these steps to understand how histotripsy exerts its unusually potent immune effects. First, we will quantitatively fine-tune the parameters of histotripsy tissue cavitation that cause maximally immunogenic tumor antigen release. Next, we will focus on the early induction of necroptosis to determine if this is a necessary local precursor event on which later manifestations of histotripsy immunostimulation depend. Then, we will examine the later process of CD8+ T cell-driven ferroptosis to determine if this is the mechanism by which the distant, abscopal effects of histotripsy are mediated. Finally, we will leverage mechanistic insights gained from these investigations to develop and test potential preclinical strategies with which the effects of histotripsy on tumor antigen release, necroptosis, and ferroptosis could be maximized for cancer immunotherapy. We have assembled a multidisciplinary team with expertise in FUS, immunology and cancer immunotherapy to pursue this work, which promises to reveal insights and strategies to bring the impact of cancer immunotherapy to a wider range of patients in need of cure.

项目摘要/摘要 免疫疗法对引起免疫认可的癌症可能非常有效 系统（例如，黑色素瘤），但它仍然是对免疫检测几乎看不见的癌症的无效 （例如胰腺癌）。癌症免疫疗法的进步将需要干预措施，使癌症成为癌症 免疫系统更明显。越来越多的证据表明，聚焦超声（FUS） 肿瘤消融可能是干预措施。通过非侵入性破坏癌细胞，热和机械 已显示FUS的模式可引发针对肿瘤的潜在免疫反应。我们有 发现Histotipy是一种非热的机械FUS模式，刺激了强大而全身的抗肿瘤 免疫反应足以引起远处，非燃烧肿瘤部位的潜线回归 - 效果不是 通常可以通过传统疗法（如辐射或热消融）来看见。组织疗法是一项技术 目前被引入临床用途；因此，必须了解机械的 组织疗法免疫刺激的基础。我们的初步研究指出了一系列逐步的事件 可以解释这一现象。首先，组织疗法导致在A中释放亚细胞癌细胞抗原 保留其免疫原性的方式。其次，组织疗法诱导癌细胞进行A 细胞自杀的特定途径称为坏死性 - 一种吸引注射和免疫的死亡途径 注意，有效地启动免疫系统以识别癌症抗原。接下来是一个进步的 CD8+ T细胞浸润到远处的肿瘤中，伴随着另一种称为癌细胞死亡的途径 铁毒性 - 最近发现的死亡途径是免疫疗法促进的关键机制 CD8+ T细胞杀死癌细胞。 在此提案中，我们将回顾以下步骤，以了解组织练习如何导出其不寻常的有效性 免疫作用。首先，我们将定量地调整导致组织肌肉组织空化的参数 最大免疫原性肿瘤抗原释放。接下来，我们将重点介绍坏死作用的早期诱导 确定这是否是必要的局部前体事件 免疫刺激取决于。然后，我们将检查CD8+ T细胞驱动的铁凋亡的后期过程 确定这是否是介导远处的，脱落效果的机制。最后，我们 将利用从这些投资中获得的机械见解来开发和测试潜在的临床前 组织疗法对肿瘤抗原释放，坏死和铁凋亡的影响的策略可能是 最大化癌症免疫疗法。我们已经组建了一个具有FUS专业知识的多学科团队， 免疫学和癌症免疫疗法以追求这项工作，该工作有望揭示见解和策略 将癌症免疫疗法的影响带入需要治愈的广泛患者。