Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer

Abstract

A phase-I trial to assess the safety and tolerability of human interleukin-12 (IL-12) plasmid (phIL-12) formulated with a synthetic lipopolymer, polyethyleneglycol-polyethyleneimine-cholesterol (PPC), was conducted on women with chemotherapy-resistant recurrent ovarian cancer. A total of 13 patients were enrolled in four dose-escalating cohorts and treated with 0.6, 3, 12 or 24 mg m À2 of the formulated plasmid once every week for 4 weeks. Administration of phIL-12/PPC was generally safe and well-tolerated. Common side effects included low-grade fever and abdominal pain. Stable disease and reduction in serum CA-125 levels were clinically observed in some patients. Measurable levels of IL-12 plasmid were detectable in PF samples collected throughout the course of phIL-12/PPC treatment. In comparison, serum samples either did not contain detectable amounts of plasmid DNA or contained o1% of the amount found in the corresponding PF samples. Treatment-related increases in IFN-g levels were observed in PF but not in serum. These data demonstrate that IL-12 gene delivery with a synthetic delivery system is feasible for ovarian cancer patients.

New insights into IL-12-mediated tumor suppression

“…133 Low levels of toxicity were also achieved when delivering an IL-12 plasmid formulated with a synthetic lipopolymer (EGEN-001) to patients with ovarian cancer. 134 The evaluation of EGEN-001 in a subsequent Phase II trial, however, only showed limited activity as well as increased toxicity in patients resistant to platinum. 135 Taken together, systemic administration of IL-12 was tested extensively and failed, barring all future attempts in this direction.…”

Neoadjuvant immunotherapy with chitosan and interleukin-12 to control breast cancer metastasis

“…18,19 In particular, non-viral IL-12-based approaches, with or without assistance from liposomes or electroporation, have shown antitumor efficacy in preclinical studies 20,21 and safety in clinical studies. 22,23 Because plasmid-based methods require translation to produce IL-12, the amount or dose of IL-12 in the tumor microenvironment from patient to patient will vary depending on the number and type of cells that are transfected.…”

Interleukin 12: Stumbling Blocks and Stepping Stones to Effective Anti-Tumor Therapy

“…This approach is attractive because of the ability of nanoparticles to transport larger amounts of genetic material than viral vectors, as well as the ability of this approach to bypass the induction of an endogenous immune response as is the case with viral vectors (93). However, nanoparticles lack the specificity required to home to sites of tumor (92). Intraperitoneal administration of this IL-12 gene bearing nanoparticle was well-tolerated, with mild to moderate fevers and abdominal pain reported for each patient.…”