BACKGROUND: Live attenuated vaccine strain of measles virus (MV) has promising antitumor activity and is undergoing clinical testing in three different phase I cancer trials. The virus uses one of two receptors, CD46 which is ubiquitously expressed on all nucleated cells or CD150 which is expressed on immune cells, to infect cells. To minimize potential toxicity due to indiscriminate infection of normal cells, we have generated a fully retargeted MV that infects cells exclusively through the prostate-specific membrane antigen (PSMA) receptor, which is overexpressed on prostate cancer cells and tumor neovasculature. METHODS: A single-chain antibody (scFv) specific for the extracellular domain of PSMA (J591) was inserted as a C-terminal extension on the MV attachment protein. Specificity of infection by the PSMA targeted virus was evaluated in parallel with the parental MV and a control virus which binds to CD38, a myeloma antigen. Antitumor activity of the PSMA retargeted virus was tested in both LNCaP and PC3-PSMA tumor xenograft models, with and without low dose external beam radiation. RESULTS: Replication of the PSMA targeted virus was comparable to the parental MV. The PSMA scFv efficiently redirected virus infection and cytopathic killing exclusively to PSMA positive prostate cancer cells and not PSMA negative cells. There was an additive effect on cell killing from radiation treatment and virotherapy. The PSMA virus induced tumor regression of LNCaP and PC3-PSMA tumor xenografts. Extensive areas of MV infection and apoptosis were seen in virus treated tumors. CONCLUSIONS: The PSMA retargeted virus warrants further investigation as a virotherapy agent. (c) 2009 Wiley-Liss, Inc.
BACKGROUND: Live attenuated vaccine strain of measles virus (MV) has promising antitumor activity and is undergoing clinical testing in three different phase I cancer trials. The virus uses one of two receptors, CD46 which is ubiquitously expressed on all nucleated cells or CD150 which is expressed on immune cells, to infect cells. To minimize potential toxicity due to indiscriminate infection of normal cells, we have generated a fully retargeted MV that infects cells exclusively through the prostate-specific membrane antigen (PSMA) receptor, which is overexpressed on prostate cancer cells and tumor neovasculature. METHODS: A single-chain antibody (scFv) specific for the extracellular domain of PSMA (J591) was inserted as a C-terminal extension on the MV attachment protein. Specificity of infection by the PSMA targeted virus was evaluated in parallel with the parental MV and a control virus which binds to CD38, a myeloma antigen. Antitumor activity of the PSMA retargeted virus was tested in both LNCaP and PC3-PSMA tumor xenograft models, with and without low dose external beam radiation. RESULTS: Replication of the PSMA targeted virus was comparable to the parental MV. The PSMAscFv efficiently redirected virus infection and cytopathic killing exclusively to PSMA positive prostate cancer cells and not PSMA negative cells. There was an additive effect on cell killing from radiation treatment and virotherapy. The PSMA virus induced tumor regression of LNCaP and PC3-PSMA tumor xenografts. Extensive areas of MV infection and apoptosis were seen in virus treated tumors. CONCLUSIONS: The PSMA retargeted virus warrants further investigation as a virotherapy agent. (c) 2009 Wiley-Liss, Inc.
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