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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

基本信息

批准号：
7615506
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
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615506
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 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 Malignant Neoplasm Malignant Neoplasms Mayo Clinic Cancer Center Mediating Metastatic Melanoma Methodology Methods Modality Modeling Modification Monitor Needles Neoplasm Metastasis Office Visits Operative Surgical Procedures Organism Patients Peptides Phase Phase I Clinical Trials Pre-Clinical Model Procedures Production Radiofrequency Interstitial Ablation Research Personnel Resource Sharing Safety Site Staging T-Lymphocyte Technology Temperature Testing Therapeutic Therapeutic Clinical Trial Time Toxic effect Translating Tumor Antigens Tumor Immunity Up-Regulation Vaccines Viral Tumor Antigens base cancer therapy clinical efficacy clinical practice cohort cold temperature effective therapy heat injury heat stimulus high risk image guided intervention in vivo instrumentation melanoma neoplastic cell palliation pathogen patient population peripheral blood pilot trial protein complex protein expression protein function public health relevance response sialosyl-T antigen treatment site treatment strategy tumor

项目摘要

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(申请人提供)：影像引导的转移性癌症介入治疗在临床上用于缓解症状性转移或消融有限的转移疾病。只有在“局部治疗”能够产生“全身性抗肿瘤”活性的情况下，才有可能将这种治疗方法应用于广泛转移的癌症。在这里，我们建议利用传统射频消融术(RFA)的改进作为一种方法，在转移性黑色素瘤患者中创建基于热休克蛋白(HSP)的内源性自体肿瘤疫苗。通过模拟体外产生HSP的条件(在42-50oC加热30min)，使用放置在肿瘤块中的RFA探针，我们建议在体内产生一种自体肿瘤疫苗。拟议的“原则证明”I期临床试验将评估改良的RFA(“热休克”)的安全性和免疫效果，随后是：(1)瘤内注射GM-CSF(免疫佐剂，队列1)；(2)常规RFA(破坏细胞膜并释放HSP)，然后瘤内注射GM-CSF(队列2)；或(3)冷冻消融(破坏细胞膜)，然后瘤内注射GM-CSF(队列3)。应计将以循序渐进的方式进行。每个患者都将接受一个肿瘤部位的治疗，然后在3周和6周后进行两次办公室访问。毒性将使用NCI-CTC标准3.0版进行跟踪。免疫效果将在外周血(肿瘤抗原特异性细胞毒性T淋巴细胞的频率)以及肿瘤部位(肿瘤细胞HSP表达上调，已治疗和未治疗肿瘤的CTL浸润&)中确定。临床疗效数据(肿瘤反应)将只是描述性的。我们已经生成了初步数据，证明改良的RFA是安全的，能够产生系统性抗肿瘤免疫。这项拟议的研究建立在研究人员在RFA、黑色素瘤免疫疗法临床研究的实验室监测和黑色素瘤临床试验方面的专业知识的基础上。试验将在梅奥临床癌症中心和综合临床研究中心的背景下进行，利用那里的共享资源/核心设施。如果成功地产生了基于热休克蛋白的内源性抗黑色素瘤疫苗，最有效的方法(队列)将转化为转移性黑色素瘤患者的II期治疗临床试验。与公共卫生相关：在临床实践中，越来越多的人使用影像引导、针头为基础的介入性治疗程序来代替高危手术切除，对局部癌症进行明确的治疗。到目前为止，这种干预措施只被考虑用于局部肿瘤的治疗，很少考虑播散性恶性肿瘤患者的治疗。在此，我们提出了一项临床试验，以改进现有的图像引导干预技术，目的是在患者的肿瘤内产生自体肿瘤疫苗，从而产生全身抗肿瘤免疫，从而治疗全身播散的恶性肿瘤。