Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma.

Abstract

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-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.

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 26 Issue 36 Pg. 5896-903 (Dec 20 2008) ISSN: 1527-7755 [Electronic] United States
• PMID: 19029422 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-12

Topics

• Adult
• Aged
• Aged, 80 and over
• Electroporation (methods)
• Female
• Genetic Therapy (methods)
• Humans
• Interleukin-12 (analysis, genetics)
• Male
• Melanoma (pathology, therapy)
• Middle Aged
• Neoplasm Metastasis
• Plasmids (administration & dosage, adverse effects)
• Skin Neoplasms (therapy)
• Treatment Outcome