Systemic auto-immunization against cancer using modified radiofrequency ablation

点击翻译按钮获取中文摘要

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.