This trial represents the first in-human testing of an oncolytic engineered MV strain as an anticancer agent. We chose recurrent ovarian cancer as our first target because of high levels of expression of the MV CD46 receptor, the possibility of delivering the viral therapy in a “confined” compartment, and the high mortality of this disease with immediate need for development of novel therapeutics. We showed excellent safety of this oncolytic virus following i.p. administration. No DLT was observed in doses up to 109 TCID50 and no immunosuppression. Most common toxicities were mild (grade 2) abdominal pain and fatigue and grade 1 fever at the absence of neutropenia. Two additional trials of engineered MV strain, a trial of intratumoral administration of MV-CEA in patients with recurrent glioblastoma multiforme and a trial of i.v. administration of the measles derivative MV-NIS in patients with multiple myeloma, have since been activated. No DLT has been observed in doses up to 107 TCID50 in the GBM trial and 109 TCID50 in the myeloma study, further highlighting the safety of MV as an oncolytic platform.
Our study represents the second reported clinical trial of a replicating oncolytic virus in recurrent ovarian cancer patients. In an earlier study, Vasey and colleagues (11
) administered i.p. the conditionally replicating adenovirus ONYX-015. Although safe, there was no evidence of antitumor activity (11
). The low or variable expression of the adenoviral receptor CAR in primary ovarian cancer cells can possibly explain this lack of efficacy (37
). In contrast, in our trial, despite the accrual of heavily pretreated patients (median number of three prior chemotherapy regimens for recurrent disease) and the fact that a very low starting dose was man-dated by the regulatory authorities (the first dose level was 10-fold lower than the dose of infectious viruses used for measles vaccination), the observed, dose-dependent disease stabilization with median duration of 92 days (54–277) days, tumor marker CA-125 responses in 5 patients, and the doubling of median survival in this phase I trial, as compared with the expected survival in this study population (36
), points toward the promising potential of oncolytic measles therapy in recurrent ovarian cancer patients. Furthermore, these data in conjunction with the observed overexpression of the MV-CEA receptor CD46 in the majority of the study patients underscore the potential importance of CD46 targeting in ovarian cancer therapeutics.
Patients in our trial were required to be measles immune to increase safety in this first human testing of the virus. Of note, however, there was no significant change in the titers of anti-MV antibody following treatment initiation, despite repeat dosing, this likely being the result of high serum antibody levels at baseline in study patients. Furthermore, in CA-125 responders, continuous CA-125 decrease following repeat dosing was observed () and points toward the value of repeat viral administration even in the setting of pre-existing immunity. One of the trial end points was detection of marker CEA as a correlate of viral gene expression. As expected, detection of CEA was dose dependent. CEA was detected in the peritoneal fluid of patients treated with a viral dose of 108 TCID50 or higher and in the serum of patients treated at the highest viral dose of 109 TCID50. Of note, eligible patients were required to have normal CEA levels so that CEA elevation observed in this study could only represent a reflection of viral replication. In general, elevation of CEA in the serum of study patients was modest (12–18 ng/mL) and recurred, although at lower levels following repeat viral administration. Given the lack of detection of anti-CEA antibodies in the study patients, this observation could be indicative of decreased viral spread associated with repeat administration.
Another factor negatively affecting the likelihood of significant CEA elevation in the serum of patients treated with MV-CEA i.p. is the dilution that occurs when CEA produced in the peritoneal cavity equilibrates into the bloodstream or extracellular fluid. In this context, a different marker gene that remains localized following expression in infected cells could represent a better correlate of viral gene expression. We are currently conducting a phase I trial of i.p. administration of MV-NIS (39
), an MV derivative encoding the sodium-iodine symporter gene (NIS, an iodine transporter), in recurrent ovarian cancer patients. NIS allows the use of iodine or technetium isotopes for imaging, using computed tomography single-photon emission computed tomography or positron emission tomography scan, and radioactive iodine isotopes for therapy.
In addition to the ongoing phase I trial of i.p. administration of MV-NIS virus, which sets the stage for the use of a measles virus-encoded therapeutic transgene, i.e., the NIS gene, we are developing technologies that can lead to further improvement of MV delivery and viral spread in ovarian tumors, including retargeting (40
), use of infected cell carriers (41
), and combination with cyclophosphamide, an immunomodulatory agent able to suppress innate immune response. The ongoing phase I MV-NIS study and the additional preclinical work currently ongoing will allow us to determine the most promising follow-up clinical step.
In summary, in this first human trial of an oncolytic MV strain in the treatment of recurrent ovarian cancer, we have shown both safety and early, promising biological activity. This oncolytic virus platform warrants further investigation in the treatment of recurrent ovarian cancer.