Abstract 2078: Interleukin-12 gene therapy in combination with bevacizumab and pegylated liposomal doxorubicin for treatment of disseminated ovarian cancer

Abstract

Despite recent improvements in treatment options for ovarian cancer patients, notably, the approval of using bevacizumab in combination with chemotherapies including pegylated liposomal doxorubicin (PLD), this disease is still the most deadly of all gynecological malignancies requiring new and novel therapeutics. Interleukin-12 (IL-12) is a highly active cytokine that can induce a potent anti-cancer immunity mediated through activation of cytotoxic T-lymphocytes, natural killer cell proliferation, and secretion of interferon-γ. We are developing an IL-12 based gene therapy for the treatment of gynecological malignancies that have spread into the peritoneal cavity. Our approach utilizes IL-12 plasmid (pIL-12) formulated with the PPC delivery system, which is comprised of a low molecular weight polyethylenimine covalently linked to polyethyleneglycol and cholesterol. Previously we have shown in a mouse model of disseminated ovarian cancer efficacy of a treatment regimen of pIL-12/PPC used in combination with paclitaxel and carboplatin. The combination treatment significantly improved survival compared to either pIL-12/PPC alone or chemotherapy alone and demonstrated the feasibility of using an IL-12 immunotherapy in combination with cytotoxic chemotherapies to achieve additive therapeutic effects. Results from a Phase I clinical trial in platinum resistant patients have shown that intraperitoneal delivery of pIL-12/PPC in combination with PLD produced an overall clinical benefit of 57.1% (PR=21.4%; SD=35.7%) in patients with measurable disease. The highest percentage of PRs were found at the highest dose level (28.6%) along with highest percentage of patients achieving SD (57.1%). Here we describe studies evaluating the combination of pIL-12/PPC with bevacizumab and PLD. For these studies 7,000,000 human SKOV-3 cells were implanted into the peritoneal cavity of immunocompromised Hsd:Athymic Nude-Foxn1nu mice. Treatment with pIL-12/PPC alone and bevacizumab alone resulted in a 50% and a 39% reduction of animals with visible tumors at the end of the study. Combining pIL-12/PPC + bevacizumab improved the response to 78% of animals with no visible tumors. Further, combining pIL-12/PPC + bevacizumab + PLD resulted in a >98% decrease in tumor burden in animals compared to controls and ~92% decrease in tumor burden compared to animals treated only with bevacizumab + PLD. All treatments were well tolerated and analysis of serum chemistries and hematology showed normal ranges of all parameters examined for all groups. There were no significant differences in animal weights between groups during the experiment. Together these results suggest synergistic efficacies can be achieved by combining a novel pIL-12/PPC immunotherapy with anti-angiogenesis therapies and cytotoxic chemotherapies in disseminated ovarian cancer.

GEN-1 Immunotherapy for the Treatment of Ovarian Cancer

“…pmIL-12/PPC significantly improved the activity of bevacizumab and pegylated liposomal doxorubicin (PLD) treatment. As shown in Figure 6, pmIL-12/PPC at 100 μg DNA alone produced 50% inhibition of tumor growth, and in the same study, bevacizumab alone also produced tumor inhibition at all three doses tested (5 [low], 10 [medium] and 20 mg/kg [high]) [47]. Addition of pmIL-12/PPC potentiated bevacizumab activity at all three doses.…”

“…In another study, the impact on efficacy of adding pmIL-12/PPC to bevacizumab plus PLD, a standard platinum-resistant ovarian cancer regimen, was explored. In the same mouse model but with cancer cells expressing luciferase gene, combination treatment with PLD (7.5 mg/kg) plus bevacizumab (10 mg/kg) produced marginal tumor response, but the addition of pmIL-12/PPC dramatically improved the response to over 90% (Figure 7) [47]. The addition of pmIL-12/PPC did not significantly influence the animal weight gain, serum chemistry or hematology profile in healthy mice (data not shown).…”