Chemoimmunotherapy Using Pegylated Liposomal Doxorubicin and Interleukin-18 in Recurrent Ovarian Cancer: A Phase I Dose-Escalation Study

Abstract

Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m 2 ) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 mg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 mg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 mg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. Cancer Immunol Res; 1(3); 168-78. Ó2013 AACR.

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

“…Clinical trials have shown that rhIL18 can be given safely and is biologically active in patients (21,22). However, these studies only focused on the IL18 0 s promotive effect on the immune system and did not examine its effect on tumor cells.…”

Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies

“…Indeed, several nanoparticles are currently on the market, including doxorubicin liposomes (Doxil; Janssen) for the treatment of ovarian cancer and AIDS-associated Kaposi’s sarcoma 24,25 , and paclitaxel-containing albumin nanoparticles (Abraxane; Celgene) for second-line treatment of patients with breast cancer 26,27 .…”

IL-18 Acts in Synergy with IL-7 To Promote Ex Vivo Expansion of T Lymphoid Progenitor Cells

“…Furthermore, the duration and dose of IL-7 necessary for effect pose a risk of graft versus host disease (GVHD) due to its ability to enhance T cell functions (48, 51). IL-18 has also been put into the spotlight for its potential role in cancer treatment and is showing promising results in pre-clinical and clinical studies (52–54). Based on the robust synergistic effects observed in our assays and the recently reported effects of IL-18 in driving homeostatic expansion of naïve CD8 T cells in lymphopenic mice (37), it is possible that combining IL-18 and IL-7 as a combination therapy in humans could overcome the limitations of IL-7, by enhancing the IL-7 effects on bone marrow and thymus progenitor cells and decreasing the dose and duration of IL-7 needed for lymphocyte reconstitution in clinical scenarios of lymphodepletion.…”