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：
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
项目类别：
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

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（由申请人提供）：用于治疗转移性癌症的图像引导介入手术在临床上用于缓解症状转移或消融有限的转移性疾病。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治疗广泛转移的癌症。在此，我们建议利用传统射频消融（RFA）的改进作为在转移性黑色素瘤患者中制造基于内源性热休克蛋白（hsp）的自体肿瘤疫苗的方法。通过使用放置在肿瘤块中的 RFA 探针模拟体外 hsp 生成条件（在 42-50oC 加热 30 分钟），我们建议在患者体内生成自体肿瘤疫苗。拟议的“原理验证”I 期临床试验将评估改良 RFA（“热休克”）的安全性和免疫功效，然后进行：（1）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 hsp），然后进行瘤内 GM-CSF（队列 2）； (3) 冷冻消融（破坏细胞膜），然后进行瘤内 GM-CSF（第 3 组）。应计费用将以逐步的方式进行。每位患者将接受单个肿瘤部位的治疗，并在 3 周和 6 周后进行两次就诊。将使用 NCI-CTC 标准 3.0 版来跟踪毒性。免疫效果将通过外周血（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 表达的上调、治疗和未治疗肿瘤的 CTL 浸润）来确定。临床疗效数据（肿瘤反应）仅是描述性的。我们已经生成了初步数据，证明改良 RFA 是安全的并且能够产生全身抗肿瘤免疫力。拟议的研究建立在研究人员在 RFA、黑色素瘤免疫治疗临床研究的实验室监测和黑色素瘤临床试验的专业知识的基础上。该试验将在梅奥诊所癌症中心和普通临床研究中心利用其中的共享资源/核心设施进行。如果成功地生产出基于内源性抗黑色素瘤热休克蛋白的疫苗，最有效的方法（队列）将转化为针对转移性黑色素瘤患者的 II 期治疗临床试验。公共健康相关性：临床实践中越来越多地使用图像引导、针刺介入手术来对局部癌症进行根治性治疗，以代替高风险的手术切除。迄今为止，此类干预措施仅考虑用于治疗局部肿瘤，很少考虑治疗播散性恶性肿瘤患者。在此，我们提出了一项临床试验，以修改现有的图像引导干预技术，以便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力，从而治疗全身的播散性恶性肿瘤。