Prostate-specific membrane antigen retargeted measles virotherapy for the treatment of prostate cancer

Chunsheng Liu, Kosei Hasegawa, Stephen J Russell, Michel Sadelain, Kah-Whye Peng

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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 retargetedMVthat 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.

Original languageEnglish (US)
Pages (from-to)1128-1141
Number of pages14
JournalProstate
Volume69
Issue number10
DOIs
StatePublished - Jul 1 2009

Fingerprint

Measles
Prostatic Neoplasms
Measles virus
Viruses
Oncogenic Viruses
Virus Diseases
Heterografts
human glutamate carboxypeptidase II
Neoplasms
Radiation
Virus Attachment
Single-Chain Antibodies
Attenuated Vaccines
Antigen Receptors
Infection
Apoptosis

Keywords

  • Oncolytic measles virus
  • Prostate cancer
  • PSMA targeting
  • Radiation

ASJC Scopus subject areas

  • Urology
  • Oncology
  • Medicine(all)

Cite this

Prostate-specific membrane antigen retargeted measles virotherapy for the treatment of prostate cancer. / Liu, Chunsheng; Hasegawa, Kosei; Russell, Stephen J; Sadelain, Michel; Peng, Kah-Whye.

In: Prostate, Vol. 69, No. 10, 01.07.2009, p. 1128-1141.

Research output: Contribution to journalArticle

Liu, Chunsheng ; Hasegawa, Kosei ; Russell, Stephen J ; Sadelain, Michel ; Peng, Kah-Whye. / Prostate-specific membrane antigen retargeted measles virotherapy for the treatment of prostate cancer. In: Prostate. 2009 ; Vol. 69, No. 10. pp. 1128-1141.
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AB - 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 retargetedMVthat 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.

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