Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

Abstract

Because of their ability to replicate, the dose-response relationships of oncolytic viruses cannot easily be predicted. To better understand the pharmacokinetics of virotherapy in relation to viral dose and schedule, we administered MV-CEA intraperitoneally in an orthotopic mouse model of ovarian cancer. MV-CEA is an attenuated oncolytic measles virus engineered to express soluble human carcinoembryonic antigen (CEA), and the virus is currently undergoing phase I clinical testing in patients with ovarian cancer. Plasma CEA levels correlate with numbers of virus-infected tumor cells at a given time, and were used as a surrogate to monitor the profiles of viral gene expression over time. The antineoplastic activity of single-or multiple-dose MV-CEA was apparent over a wide range of virus doses (10 3 -10 8 TCID 50 ), with little reduction in observed antitumor efficacy, even at the lowest tested dose. However, analysis of CEA profiles of treated mice was highly informative, illustrating the variability in virus kinetics at different dose levels. The highest doses of virus were associated with higher initial levels of tumor cell killing, but the final outcome of MV-CEA therapy at all dose levels was a partial equilibrium between virus and tumor, resulting in significant slowing of tumor growth and enhanced survival of the mice.

A Multiscale Mathematical Model for Oncolytic Virotherapy

“…Unfortunately, in these phase I and phase II clinical trials with 11% and 14% of positive responses, respectively, it was not reported if the tumor growth progress either in a monotonic or oscillatory way. A neat indication of such oscillatory tumor growth is observed in an ovarian cancer xenograft model attacked with MV-CEA (an engineered measles virus) administered intratumorally (27). By contrast, vaccinia viruses have induced durable complete responses in patients after intratumoral or even i.v.…”

Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas

“…First, proliferation of uninfected tumor cells must have outpaced the spread of MV, in line with recent findings in experimental ovarian carcinoma. 24 It remains to be determined whether attenuation of the spread of MVEdm contributes to this. Second, the presence of foci of persistent MV-Edm infection without cytopathic effect suggests resistance of tumor cells to MV-Edm-induced cell death.…”

Questing for an optimal, universal viral agent for oncolytic virotherapy

“…Furthermore, the last behavior can be either a monotonic or an oscillating growth. It is worthy to notice that such oscillations were observed in human myeloma xenografts induced in mice treated with measles virus (MV) [23], in an ovarian cancer xenograft model [24], and in a mathematical approach used by Dingli et al for modeling MV virotherapy [25]. The therapeutic outcome depends on both viral characteristics and tumor dynamics.…”