Systemic auto-immunization against cancer using modified radiofrequency ablation

使用改良射频消融进行全身性抗癌自身免疫

• 批准号: 7498353
• 负责人: SVETOMIR Nenad MARKOVIC
• 金额: $ 34万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498353
• 关键词: Ablation; Anecdotes; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autologous; Cancer Vaccines; Cell membrane; Cells; Clinical; Clinical Research; Clinical Trials; Cold Therapy; Complex; Condition; Core Facility; Cryosurgery; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Disseminated Malignant Neoplasm; Excision; Figs - dietary; Frequencies; Generations; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-A2 Antigen; Heat shock proteins; Heat-Shock Response; Heating; Image; Immune response; Immunity; Immunization; Immunologic Adjuvants; Immunotherapy; In Vitro; Infiltration; Inflammatory; Injection of therapeutic agent; Intervention; Invaded; Laboratories; Local Therapy; Localized; Localized Malignant Neoplasm; Malignant Neoplasms; Mayo Clinic Cancer Center; Mediating; Metastatic Melanoma; Methodology; Methods; Modality; Modeling; Modification; Monitor; Needles; Neoplasm Metastasis; Numbers; Office Visits; Operative Surgical Procedures; Organism; Patients; Peptides; Phase; Phase I Clinical Trials; Population; Pre-Clinical Model; Procedures; Production; Public Health; Purpose; Radiofrequency Interstitial Ablation; Research Personnel; Resource Sharing; Risk; Safety; Site; Staging; T-Lymphocyte; Technology; Temperature; Testing; Therapeutic; Therapeutic Clinical Trial; Time; Toxic effect; Transcriptional Activation; Translating; Tumor Antigens; Tumor Immunity; Up-Regulation; Vaccines; Viral Tumor Antigens; Week; base; cancer therapy; clinical efficacy; cohort; cold temperature; heat injury; heat stimulus; image guided intervention; in vivo; instrumentation; melanoma; neoplastic cell; pathogen; peripheral blood; pilot trial; protein expression; protein function; response; sialosyl-T antigen; treatment site; tumor

DESCRIPTION (provided by applicant): Image-guided interventional procedures for the treatment of metastatic cancer are clinically utilized for palliation of symptomatic metastases or ablation of limited metastatic disease. The application of this therapeutic modality for the treatment of widely metastatic cancer is only possible if "local therapy" can result in "systemic anti-tumor" activity. Herein, we propose to utilize a modification of conventional radiofrequency ablation (RFA) as a means of creating an endogenous, heat-shock protein (hsp) based autologous tumor vaccine in patients with metastatic melanoma. By mimicking in vitro conditions for hsp generation (heating at 42-50oC for 30min) using an RFA probe placed into a tumor mass, we propose to generate an autologous tumor vaccine in patients in vivo. The proposed "proof-of-principle" phase I clinical trial will evaluate the safety and immunization efficacy of modified RFA ("heat-shock") followed by either: (1) intratumoral GM-CSF injection (immune adjuvant, cohort 1); (2) conventional RFA (disrupt cell membranes and release hsp) followed by intratumoral GM-CSF (cohort 2); or (3) cryoablation (disrupt cell membranes) followed by intratumoral GM-CSF (cohort 3). Accrual will proceed in step-wise fashion. Each patient will undergo treatment of a single tumor site, followed by two office visits 3 and 6 weeks later. Toxicity will be followed using NCI-CTC criteria version 3.0. Immunization efficacy will be ascertained in peripheral blood (frequency of tumor-antigen specific cytotoxic T lymphocytes) as well as the tumor site (up-regulation of tumor cell hsp expression, CTL infiltration of treated and untreated tumors&). Clinical efficacy data (tumor response) will be only descriptive. We've generated preliminary data demonstrating that modified RFA is safe and capable of generating systemic anti- tumor immunity. The proposed study builds on the expertise of the investigators in RFA, laboratory monitoring of melanoma immunotherapy clinical studies and conduct of melanoma clinical trials. The trial will take place in the context of the Mayo Clinic Cancer Center and General Clinical Research Center utilzing shared resources/core facilities therein. If successful in generating endogenous anti-melanoma hsp based vaccines, the most effective method (cohort) will be translated into a phase II therapeutic clinical trial for patients with metastatic melanoma. PUBLIC HEALTH RELEVANCE: Image guided, needle based, interventional procedures by which patients undergo definitive therapy of localized cancers in lieu of higher-risk surgical resections are increasingly utilized in clinical practice. To date, such interventions are only considered for treatment of localized tumors with little consideration in patients with disseminated malignancies. Herein, we propose a clinical trail to modify existing technology of image-guided interventions for the purpose of generating autologous cancer vaccines within the patient's tumors leading to systemic anti-tumor immunity thereby treating the disseminated malignancy throughout the body.

描述（由申请人提供）：用于治疗转移性癌症的图像引导的干预程序在临床上用于抑制症状转移或消融有限的转移性疾病。只有在“局部治疗”可以带来“全身性抗肿瘤”活性的情况下，这种治疗方式在治疗广泛转移性癌症的治疗中才有可能。本文中，我们建议利用常规射频消融（RFA）的修饰，作为在转移性黑色素瘤患者中创建基于内源性的，热震蛋白（HSP）自体肿瘤疫苗的手段。通过模仿将HSP生成的体外条件（30分钟以42-50OC的加热）使用RFA探针放入肿瘤肿块中，我们建议在体内患者生成一种自体肿瘤疫苗。拟议的“原理证明” I期临床试验将评估改性RFA（“热震”）的安全性和免疫功效，其次是：（1）肿瘤内GM-CSF注射（免疫辅助剂，共生1）； （2）常规RFA（破坏细胞膜和释放HSP），然后是肿瘤内GM-CSF（同类群体2）；或（3）冷冻（破坏细胞膜），然后是肿瘤内GM-CSF（队列3）。应计将以逐步进行。每个患者将接受一个单个肿瘤部位的治疗，然后在3周和6周后进行两次办公室访问。使用NCI-CTC标准3.0版将遵循毒性。将在外周血（肿瘤抗原特异性细胞毒性T淋巴细胞的频率）和肿瘤部位（肿瘤细胞HSP表达上调，治疗和未治疗的肿瘤的CTL浸润和未治疗的肿瘤及）中确定免疫功效。临床疗效数据（肿瘤反应）仅具有描述性。我们已经生成了初步数据，表明修饰的RFA是安全的，并且能够产生全身性抗肿瘤免疫。拟议的研究以RFA研究人员的专业知识，黑色素瘤免疫疗法临床研究的实验室监测以及黑色素瘤临床试验的进行为基础。该试验将在梅奥临床癌症中心和一般临床研究中心的背景下进行，其中包括共享资源/核心设施。如果成功地产生了基于内源性抗黑色素HSP的疫苗，则最有效的方法（队列）将被转化为转移性黑色素瘤患者的II期治疗临床试验。公共卫生相关性：图像指导，基于针头的介入程序，通过该程序，患者对局部癌症进行明确治疗以代替高危手术切除术，越来越多地用于临床实践。迄今为止，这种干预措施仅用于治疗局部肿瘤，而在传播恶性肿瘤的患者中很少考虑。在此，我们提出了一条临床步道，以修改图像引导的干预措施的现有技术，目的是在患者的肿瘤内产生自体癌疫苗，从而导致全身性抗肿瘤免疫，从而治疗整个人体的传播恶性肿瘤。