Originally published as JCO Early Release 10.1200/JCO.2007.15.6794 on November 24 2008

This Article Full Text Full Text (PDF) Publisher's Note Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Daud, A. I. Articles by Heller, R. Search for Related Content PubMed PubMed Citation Articles by Daud, A. I. Articles by Heller, R. Social Bookmarking                            What's this?

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

Adil I. Daud, Ronald C. DeConti, Stephanie Andrews, Patricia Urbas, Adam I. Riker, Vernon K. Sondak, Pamela N. Munster, Daniel M. Sullivan, Kenneth E. Ugen, Jane L. Messina, Richard Heller

From the Cutaneous Oncology and Experimental Therapeutics Programs, H. Lee Moffitt Cancer Center; and the Department of Molecular Medicine and Center For Molecular Delivery, College of Medicine, University of South Florida, Tampa, FL

Corresponding author: Adil I. Daud, MD, University of California, San Francisco, 1600 Divisadero St, MtZ A714, Box 1770, San Francisco, CA 94143; e-mail: adaud{at}medicine.ucsf.edu

Purpose 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.

Patients and Methods 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-µs 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.

Results 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.

Conclusion 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.

published online ahead of print at www.jco.org on November 24, 2008

Supported by the National Gene Vector Laboratory at the National Institutes of Health, the American Cancer Society (grant in aid to A.I.D) and Innovio Biomedical Corporation.

Presented in part at the 9th Annual Meeting of the American Society of Gene Therapy, May 31-June 4, 2006, Baltimore, MD, and at the AACR-NCI-EORTC Molecular Targets Meeting, November 7-10, 2006, Prague, Czech Republic.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00323206 [ClinicalTrials.gov] .

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?