775. Folate Receptor Targeted Virotherapy of Ovarian Cancer Using a Tropism Modified Measles Virus
Authors: Kosei Hasegawa, Takafumi Nakamura, Mary Harvey, Yashiro Ikeda, Ann Oberg, Mariangela Figini, Silvana Canevari, Lynn Hartmann, Kah-Whye Peng
Journal: Molecular Therapy (2006)

Attenuated measles viruses are being evaluated in a phase I dose escalation trial for ovarian cancer patients. The virus encodes a soluble marker protein to facilitate noninvasive monitoring of viral gene expression. This virus uses either of two measles receptors, CD46 and SLAMV for binding, entry, and subsequent intercellular fusion between infected and uninfected neighboring cells. To minimize potential toxicity due to MV-associated immunosuppression and infection of nontarget tissues, we sought to develop an ovarian cancer exclusive fully retargeted MV. Interactions of MV with its natural receptors were ablated and a single-chain antibody (scFv) specific for alpha-folate receptor (aFR), a target overexpressed on 90% of non-mucinous ovarian cancer, was genetically engineered on the viral attachment protein (MV-aFR). Specificity of virus tropism was tested on a panel of tumor and normal cells. Biodistribution of MV infection was evaluated in measles susceptible CD46 transgenic mice while anti-tumor activity was monitored non-invasively by bioluminescence imaging and tumor secreted bhCG peptide in xenograft models. All statistical tests were two-sided. Tropism and fusogenic activity of MV-aFR was redirected exclusively to FRa without compromise to virus infectivity. In contrast to the parental virus, MV-aFR has no background infectivity on normal human cells. The anti-tumor activity of MV-aFR, as assessed by tumor volume reduction and overall survival increase, was equal to the parental virus in two models of human ovarian cancer (subcutaneous and intraperitoneal). For the first time, a FR-exclusive ovarian cancer targeted oncolytic virus was generated and shown to be therapeutically effective, thus introducing a new modality for folate targeting and a candidate MV for clinical testing. Attenuated measles viruses are being evaluated in a phase I dose escalation trial for ovarian cancer patients. The virus encodes a soluble marker protein to facilitate noninvasive monitoring of viral gene expression. This virus uses either of two measles receptors, CD46 and SLAMV for binding, entry, and subsequent intercellular fusion between infected and uninfected neighboring cells. To minimize potential toxicity due to MV-associated immunosuppression and infection of nontarget tissues, we sought to develop an ovarian cancer exclusive fully retargeted MV. Interactions of MV with its natural receptors were ablated and a single-chain antibody (scFv) specific for alpha-folate receptor (aFR), a target overexpressed on 90% of non-mucinous ovarian cancer, was genetically engineered on the viral attachment protein (MV-aFR). Specificity of virus tropism was tested on a panel of tumor and normal cells. Biodistribution of MV infection was evaluated in measles susceptible CD46 transgenic mice while anti-tumor activity was monitored non-invasively by bioluminescence imaging and tumor secreted bhCG peptide in xenograft models. All statistical tests were two-sided. Tropism and fusogenic activity of MV-aFR was redirected exclusively to FRa without compromise to virus infectivity. In contrast to the parental virus, MV-aFR has no background infectivity on normal human cells. The anti-tumor activity of MV-aFR, as assessed by tumor volume reduction and overall survival increase, was equal to the parental virus in two models of human ovarian cancer (subcutaneous and intraperitoneal). For the first time, a FR-exclusive ovarian cancer targeted oncolytic virus was generated and shown to be therapeutically effective, thus introducing a new modality for folate targeting and a candidate MV for clinical testing.