Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer

Abstract

Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (10(3)-10(9) TCID(50)). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54-277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3-38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.

Figure 1

Schematic representation of MV-CEA. The cDNA encoding for the human CEA was inserted upstream of the nucleoprotein (N) gene. P, phosphoprotein gene; M, matrix protein gene; F, fusion protein gene; L, large protein gene (adapted with permission from Peng KW et al., Nat Med 2002;8:527–31).

Figure 2

Treatment-related adverse events in cycle 1. MV-CEA treatment was well tolerated with only mild (grade 1 and 2) toxicity being observed.

Figure 3

A, mean serum anti-MV antibody titers at baseline and prior to the patients going off-study, presented per dose level. No significant difference was observed between pre- and post-treatment values. B, strong expression of MV receptor CD46 in the tumors of two study patients (A and B). C, serum CEA kinetics in a patient treated at the 10⁹ TCID₅₀ dose level. CEA elevation was observed even following repeat dosing although at gradually decreasing levels.

Figure 4

CA-125 response curves in two study patients who received six (patient A) and three (patient B) treatment cycles. Continued CA-125 response was observed in response to repeat viral dosing. Patient A maintained disease stability for 8 mo (i.e., 2 mo following treatment completion), whereas patient B had extra-abdominal (central nervous system) disease progression, while on treatment.