Clinical testing of engineered oncolytic measles virus strains in the treatment of cancer: an overview

Abstract

Viruses have adapted through millennia of evolution to effectively invade and lyse cells through diverse mechanisms. Strains of the attenuated measles virus Edmonston (MV-Edm) vaccine lineage can preferentially infect and destroy cancerous cells while sparing the surrounding tissues. This specificity is predominantly due to overexpression of the measles virus receptor CD46 in tumor cells. To facilitate in vivo monitoring of viral gene expression and replication, these oncolytic strains have been engineered to either express soluble marker peptides, such as the human carcinoembryonic antigen (CEA; MV-CEA virus), or genes that facilitate imaging and therapy, such as the human thyroidal sodium iodide symporter (NIS) gene (MV-NIS). Preclinical efficacy and safety data for engineered oncolytic MV-Edm derivatives that led to their clinical translation are discussed in this review, and an overview of the early experience in three ongoing clinical trials of patients with ovarian cancer, glioblastoma multiforme and multiple myeloma is provided. The information obtained from these ongoing trials will guide the future clinical application and further development of MV strains as anticancer agents.

Figure 1. Burkitt’s lymphoma regression following measles virus infection

(A) An eight-year-old African boy with painless right orbital swelling due to Burkitt’s lymphoma. (B) The appearance of generalized measles exanthema coincided with complete tumor regression. The patient remained in complete remission for > 4 months after the measles infection. (Reproduced with permission from Elsevier Ltd and Bluming AZ, Ziegler: Regression of Burkitt's lymphoma in association with measles infection. Lancet (1971) 2(7715):105-106 © 1971 Elsevier Ltd).

Figure 2. Prominent syncytia formation of glioma cell lines following MV-CEA infection

Cells were stained using crystal violet stain (× 200 magnification). The human malignant glioma cell lines U87 and U118 were infected with measles virus (MV) expressing human carcinoembryonic antigen (CEA; MV-CEA virus), resulting in the characteristic cytopathic effect, including extensive syncytia formation. (A) Uninfected U87 cells, (B) U87 cells 120 h after infection with MV-CEA (multiplicity of infection = 0.05), (C) uninfected U118 cells, (D) U118 cells 120 h after infection with MV-CEA (multiplicity of infection = 0.05).

Figure 3. A schematic representation of MV-CEA and MV-NIS

The measles virus (MV) strain producing the human carcinoembryonic antigen (CEA; MV-CEA) was constructed with insertion of the sequence corresponding to the soluble extracellular N-terminal domain of human CEA upstream of the viral nucleocapsid (N) gene. The MV strain containing the human thyroidal sodium iodide symporter gene (NIS; MV-NIS) shares a similar vector backbone with MV-CEA except that the NIS cDNA was inserted downstream of the viral hemagglutinin (H) gene. Aat II Aat II restriction site, F viral fusion gene, L viral polymerase gene, M viral matrix gene, Mlu I an Mlu I restriction site, P viral phosphoprotein gene. (Reproduced with permission from the American Association for Cancer Research and Hasegawa K, Pham L, O'Connor MK, Federspiel MJ, Russell SJ, Peng K-W: Dual therapy of ovarian cancer using measles viruses expressing carcinoembryonic antigen and sodium iodide symporter. Clin Cancer (2006) 12(6):1868-1875 © 2006 American Association for Cancer Research).