Oncolytic herpes simplex virus (HSV) vectors have been used in early phase human clinical trials as a
therapy for recurrent malignant
glioblastoma. This treatment proved safe but limited improvements in patient survival were observed. The potency of these vectors might be enhanced by targeting vector infectivity to
tumor cells.
Glioma tumors often express a mutant form (vIII) of the
epidermal growth factor receptor (EGFR) resulting in the presence of a novel
epitope on the cell surface. This
epitope is specifically recognized by a single-chain antibody designated MR1-1. HSV-1
infection involves initial binding to
heparan sulfate (HS) on the cell surface mediated primarily by the viral envelope,
glycoprotein C (gC). Here we joined the MR1-1 single-chain antibody (scFv) to the gC sequence deleted for the HS-binding domain as a means of targeting viral attachment to
EGFRvIII on glial
tumor cells. Virions bearing MR1-1-modified gC had fivefold increased infectivity for
EGFRvIII-bearing human
glioma U87 cells compared to mutant receptor-deficient cells. Further, MR1-1/
EGFRvIII-mediated
infection was more efficient for
EGFRvIII-positive cells than was wild-type virus for either positive or negative cells. Sustained
infection of EGFRvIII+
glioma cells by MR1-1-modified gC-bearing oncolytic virus, as compared to wild-type gC oncolytic virus, was also shown in subcutaneous
tumors in vivo using
firefly luciferase as a reporter of
infection. These data show that HSV tropism can be manipulated so that virions recognize a cell-specific binding site with increased infectivity for the target cell. The retargeting of HSV
infection to
tumor cells should enhance vector specificity,
tumor cell killing and vector safety.