The Use of a Tropism-Modified Measles Virus in Folate Receptor–Targeted Virotherapy of Ovarian Cancer

• Published in: Clinical cancer research 2006-10, Vol.12 (20), p.6170-6178
• Main Authors: Hasegawa, Kosei, Nakamura, Takafumi, Harvey, Mary, Ikeda, Yasuhiro, Oberg, Ann, Figini, Mariangela, Canevari, Silvana, Hartmann, Lynn C, Peng, Kah-Whye
• Format: Article
• Language: English
• Subjects: Cancer Vaccines; Carrier Proteins - physiology; Female; folate receptor; Folate Receptors, GPI-Anchored; Genetic Vectors; Humans; Lentivirus - genetics; Lymphocytes - immunology; Measles virus; oncolytic virus; ovarian cancer; Ovarian Neoplasms - immunology; Ovarian Neoplasms - virology; Receptors, Cell Surface - physiology; Reference Values; Vaccines, Attenuated; vector targeting; Viral Vaccines
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0992

Purpose: Attenuated measles viruses are promising experimental anticancer agents currently being evaluated in a phase I dose escalation trial for ovarian cancer patients. Virus attachment, entry, and subsequent intercellular fusion between infected and uninfected neighboring cells are mediated via the two measles receptors (CD46 and SLAM). To minimize potential toxicity due to measles virus–associated immunosuppression and infection of nontarget tissues, we sought to develop an ovarian cancer exclusive fully retargeted measles virus. Experimental Design and Results: Interactions of measles virus with its natural receptors were ablated, and a single-chain antibody (scFv) specific for α-folate receptor (FRα), a target overexpressed on 90% of nonmucinous ovarian cancer, was genetically engineered on the viral attachment protein (MV-αFR). Specificity of virus tropism was tested on tumor and normal cells. Biodistribution of measles virus infection was evaluated in measles-susceptible CD46 transgenic mice, whereas antitumor activity was monitored noninvasively by bioluminescence imaging in xenograft models. Tropism and fusogenic activity of MV-αFR was redirected exclusively to FRα without compromise to virus infectivity. In contrast to the parental virus, MV-αFR has no background infectivity on normal human cells. The antitumor activity of MV-αFR, as assessed by tumor volume reduction and overall survival increase, was equal to the parental virus in two models of human ovarian cancer (s.c. and i.p.). Conclusions : A FR-exclusive ovarian cancer targeted oncolytic virus was generated and shown to be therapeutically effective, thus introducing a new modality for FR targeting and a candidate measles virus for clinical testing.