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）：用于转移性癌症治疗的图像引导介入程序在临床上用于缓解症状性转移或消融有限转移性疾病。只有当“局部治疗”能够产生“全身抗肿瘤”活性时，这种治疗方式才能应用于广泛转移性癌症的治疗。在此，我们建议利用传统射频消融（RFA）的改进作为一种方法，在转移性黑色素瘤患者中创建内源性热休克蛋白（hsp）为基础的自体肿瘤疫苗。通过将RFA探针放入肿瘤块中，模拟热休克蛋白在体外产生的条件（在42-50℃下加热30分钟），我们建议在患者体内产生一种自体肿瘤疫苗。拟议的“原理验证”I期临床试验将评估改良RFA（“热休克”）的安全性和免疫效果，然后：(1)肿瘤内GM-CSF注射（免疫佐剂，队列1）；(2)常规RFA（破坏细胞膜并释放热休克蛋白），然后进行肿瘤内GM-CSF（队列2）；或者(3)冷冻消融（破坏细胞膜），然后在肿瘤内注射GM-CSF（队列3）。应计收益将以循序渐进的方式进行。每位患者将接受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就诊。毒性将采用NCI-CTC 3.0版标准进行随访。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）和肿瘤部位（肿瘤细胞hsp表达上调，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）将仅是描述性的。我们已经生成了初步数据，证明改良的RFA是安全的，能够产生全身抗肿瘤免疫。拟议的研究建立在RFA研究人员的专业知识基础上，黑素瘤免疫治疗临床研究的实验室监测和黑素瘤临床试验的进行。该试验将在梅奥诊所癌症中心和普通临床研究中心进行，利用其中的共享资源/核心设施。如果成功产生内源性抗黑素瘤热休克蛋白疫苗，最有效的方法（队列）将转化为转移性黑素瘤患者的II期治疗性临床试验。公共卫生相关性：影像引导、针头导向、介入治疗，患者接受局部癌症的明确治疗，代替高风险的手术切除，越来越多地应用于临床实践。到目前为止，这些干预措施只考虑用于局部肿瘤的治疗，而很少考虑对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，目的是在患者肿瘤内产生自体癌症疫苗，从而产生全身抗肿瘤免疫，从而治疗全身弥散性恶性肿瘤。