Phase I Trial of Interleukin-12 Plasmid Electroporation in Patients With Metastatic Melanoma

电穿孔 医学 体内 遗传增强 免疫疗法 不利影响 不可逆电穿孔 基因传递 黑色素瘤 癌症 癌症研究 病理 外科 免疫学 内科学 基因 生物 生物技术 生物化学
作者
Adil Daud,Ronald C. DeConti,Stephanie Andrews,P. Urbas,Adam I. Riker,Vernon K. Sondak,Pamela N. Münster,Daniel M. Sullivan,Kenneth E. Ugen,Jane L. Messina,Richard Heller
出处
期刊:Journal of Clinical Oncology [American Society of Clinical Oncology]
卷期号:26 (36): 5896-5903 被引量:652
标识
DOI:10.1200/jco.2007.15.6794
摘要

Gene-based immunotherapy for cancer is limited by the lack of safe, efficient, reproducible, and titratable delivery methods. Direct injection of DNA into tissue, although safer than viral vectors, suffers from low gene transfer efficiency. In vivo electroporation, in preclinical models, significantly enhances gene transfer efficiency while retaining the safety advantages of plasmid DNA.A phase I dose escalation trial of plasmid interleukin (IL)-12 electroporation was carried out in patients with metastatic melanoma. Patients received electroporation on days 1, 5, and 8 during a single 39-day cycle, into metastatic melanoma lesions with six 100-mus pulses at a 1,300-V/cm electric field through a penetrating six-electrode array immediately after DNA injection. Pre- and post-treatment biopsies were obtained at defined time points for detailed histologic evaluation and determination of IL-12 protein levels.Twenty-four patients were treated at seven dose levels, with minimal systemic toxicity. Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two (10%) of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients (42%) showed disease stabilization or partial response.This report describes the first human trial, to our knowledge, of gene transfer utilizing in vivo DNA electroporation. The results indicated this modality to be safe, effective, reproducible, and titratable.
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