Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans.

TLDR

Direct gene transfer can introduce therapeutic DNA into patients, building on prior ex vivo cell‑modified approaches. The study aimed to determine the feasibility and safety of directly transferring genes into humans. DNA‑liposome complexes encoding HLA‑B7 were injected into HLA‑B7‑negative stage IV melanoma patients to demonstrate gene transfer, expression, and safety. Six treatment courses in five stage IV melanoma patients were completed without complications, plasmid DNA was found only in tumor biopsies, recombinant HLA‑B7 protein and immune responses were detected, no anti‑DNA antibodies appeared, and one patient showed regression of injected and distant nodules, demonstrating feasibility, safety, and therapeutic potential of direct gene transfer.

Abstract

Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.