Systemic auto-immunization against cancer using modified radiofrequency ablation

描述（由申请方提供）：转移性癌症治疗的图像引导介入手术在临床上用于缓解症状性转移或消融局限性转移性疾病。只有当“局部治疗”可以产生“全身抗肿瘤”活性时，才有可能应用这种治疗方式治疗广泛转移的癌症。在此，我们建议利用常规射频消融（RFA）的修改作为一种手段，在转移性黑色素瘤患者中创建一种内源性，热休克蛋白（hsp）为基础的自体肿瘤疫苗。通过模拟hsp生成的体外条件（在42- 50 ℃加热30分钟），使用置于肿瘤块中的RFA探针，我们建议在体内患者中生成自体肿瘤疫苗。拟议的“原理验证”I期临床试验将评估改良RFA的安全性和免疫效力（“热休克”），然后是：（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），然后瘤内注射GM-CSF（组2）;或（3）冷冻消融（破坏细胞膜），随后瘤内GM-CSF（组3）。应计将逐步进行。每例患者将接受单个肿瘤部位的治疗，然后在3周和6周后进行两次门诊访视。将使用NCI-CTC标准第3.0版对毒性进行随访。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表达的上调、经治疗和未经治疗的肿瘤的CTL浸润&）中确定免疫效力。临床疗效数据（肿瘤缓解）仅为描述性数据。我们已经生成了初步数据，证明改良RFA是安全的，能够产生全身抗肿瘤免疫。拟议的研究建立在研究者在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开展方面的专业知识基础上。本试验将在马约诊所癌症中心和综合临床研究中心进行，利用其中的共享资源/核心设施。如果成功地产生基于内源性抗黑色素瘤hsp的疫苗，最有效的方法（队列）将转化为转移性黑色素瘤患者的II期治疗性临床试验。公共卫生相关性：在临床实践中，越来越多地使用图像引导的、基于针的介入手术，通过该介入手术，患者接受局部癌症的确定性治疗，而不是高风险的手术切除。到目前为止，这种干预措施只考虑用于治疗局部肿瘤，很少考虑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，目的是在患者的肿瘤内产生自体癌症疫苗，从而产生系统性抗肿瘤免疫力，从而治疗全身的播散性恶性肿瘤。

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.