Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer

Abstract

Edmonston vaccine strains of measles virus (MV) have significant antitumor activity in mouse xenograft models of ovarian cancer. MV engineered to express the sodium iodide symporter gene (MV-NIS) facilitates localization of viral gene expression and offers a tool for tumor radiovirotherapy. Here, we report results from a clinical evaluation of MV-NIS in patients with taxol- and platinum-resistant ovarian cancer. MV-NIS was given intraperitoneally every 4 weeks for up to 6 cycles. Treatment was well tolerated and associated with promising median overall survival in these patients with heavily pretreated ovarian cancer; no dose-limiting toxicity was observed in 16 patients treated at high-dose levels (10(8)-10(9) TCID50), and their median overall survival of 26.5 months compared favorably with other contemporary series. MV receptor CD46 and nectin-4 expression was confirmed by immunohistochemistry in patient tumors. Sodium iodide symporter expression in patient tumors after treatment was confirmed in three patients by (123)I uptake on SPECT/CTs and was associated with long progression-free survival. Immune monitoring posttreatment showed an increase in effector T cells recognizing the tumor antigens IGFBP2 and FRα, indicating that MV-NIS treatment triggered cellular immunity against the patients' tumor and suggesting that an immune mechanism mediating the observed antitumor effect. Our findings support further clinical evaluation of MV-NIS as an effective immunovirotherapy.

Figure 1

Adverse events possibly, probably, or definitely related to treatment in cycle 1.

Figure 2

A, pre MV-NIS treatment biopsy from perirectal region showing high-grade serous ovarian carcinoma. B, abdominal wall nodule biopsy following six cycles of MV-NIS in the same patient. There is dense fibrosis, but no evidence of viable tumor, indicating a pathologic complete response to treatment. C and D, representative images showing overexpression of MV receptors CD46 (C) and nectin-4 (D) in tumors of study patients (brown staining).

Figure 3

No significant change in anti-MV antibody titers was observed following MV-NIS treatment. Results are presented per dose level.

Figure 4

NIS expression as imaged by I¹²³ uptake in one of the study patients; I¹²³ scan was negative at baseline (A) but became positive on day 8 of cycle 1 (B).

Figure 5

Generation of Th1 immune responses in patients with ovarian cancer undergoing treatment with MV. A–C, mean pretreatment and posttreatment IFNγ ELIspot responses for four treated patients against tumor antigens and tetanus toxoid (TT). Each symbol is calculated from 12 replicates. D, mean pre- and posttreatment antibody responses to various purified tumor antigens as well as tetanus toxoid. Each bar represents the mean (SEM) levels antibodies calculated from duplicate samples from 31 patients with ovarian cancer treated with MV.