Virotherapy of peritoneal carcinomatosis
Introduction: Peritoneal carcinomatosis (PC) is one of the most aggressive and difficult-to-treat tumor entities. We are currently recruiting patients with PC being refractory to any conventional therapy in a monocentric phase I/II study (NCT01443260) designed to assess safety, MTD, and anti-tumor activity of GL-ONC1, a recombinant Vaccinia virus (VACV) genetically engineered to selectively replicate in and destroy cancer cells.
Methods: GL-ONC1 is administered intraperitoneally up to 4 times every 28 days under a standard 3+3 dose escalation design. Safety is assessed using CTCAEv4.0. Anti-tumor activity is determined by “fluid biopsies” obtained via repetitive paracenteses and by serial PET-CT scans. Patient samples are collected for pharmacokinetics, pharmacodynamics and viral shedding analysis.
Results: Up to now, 6 patients (advanced stage PC from gastric and ovarian cancer as well as from mesothelioma) have received 12 doses of GL-ONC1. Adverse events have generally been limited to grade 1/2, including transient flu-like symptoms and increased abdominal pain as a result from treatment-induced peritonitis. No DLT has been reported. No viral shedding has been observed. In one gastric cancer patient, effective intraperitoneal replication of GL-ONC1 was demonstrated for more than 3 weeks. Of note, 3 days after virotherapeutic treatment, around 5% of all ascitic cells were found to be EpCAM-positive in this patient, and only 5 – 10% of these cancer cells were VACV-positive at the same day. In contrast, on day 7 less than 2% of all ascitic cells were still EpCAM-positive, and even more than 90% of these cancer cells were VACV-positive.
Conclusions: Preliminary data demonstrate that GL-ONC1 is well tolerated when infused intraperitoneally. Importantly, a single low dose (i.e. 107 infectious viral particles) of intraperitoneally administered GL-ONC1 was found to be sufficient to significantly reduce the number of tumor cells in the ascites.