Dendritic Cell Based PSMA Immunotherapy for Prostate Cancer Using a CD40-Targeted Adenovirus Vector

Briana Jill Williams, Shilpa Bhatia, Lisa K. Adams, Susan Boling, Jennifer L. Carroll, Xiao Lin Li, Donna L. Rogers, Nikolay Korokhov, Imre Kovesdi, Alexander V. Pereboev, David T. Curiel, James Michael Mathis

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Abstract

Human prostate tumor vaccine and gene therapy trials using ex vivo methods to prime dendritic cells (DCs) with prostate specific membrane antigen (PSMA) have been somewhat successful, but to date the lengthy ex vivo manipulation of DCs has limited the widespread clinical utility of this approach. Our goal was to improve upon cancer vaccination with tumor antigens by delivering PSMA via a CD40-targeted adenovirus vector directly to DCs as an efficient means for activation and antigen presentation to T-cells. To test this approach, we developed a mouse model of prostate cancer by generating clonal derivatives of the mouse RM-1 prostate cancer cell line expressing human PSMA (RM-1-PSMA cells). To maximize antigen presentation in target cells, both MHC class I and TAP protein expression was induced in RM-1 cells by transduction with an Ad vector expressing interferon-gamma (Ad5-IFNγ). Administering DCs infected ex vivo with CD40-targeted Ad5-huPSMA, as well as direct intraperitoneal injection of the vector, resulted in high levels of tumor-specific CTL responses against RM-1-PSMA cells pretreated with Ad5-IFNγ as target cells. CD40 targeting significantly improved the therapeutic antitumor efficacy of Ad5-huPSMA encoding PSMA when combined with Ad5-IFNγ in the RM-1-PSMA model. These results suggest that a CD-targeted adenovirus delivering PSMA may be effective clinically for prostate cancer immunotherapy.

Original languageEnglish
Article numbere46981
JournalPLoS ONE
Volume7
Issue number10
DOIs
StatePublished - 8 Oct 2012

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immunotherapy
prostatic neoplasms
Adenoviridae
dendritic cells
Immunotherapy
Dendritic Cells
Prostatic Neoplasms
antigens
antigen presentation
Antigen Presentation
neoplasms
cells
Antigens
Active Immunotherapy
Gene therapy
Cancer Vaccines
T-cells
human glutamate carboxypeptidase II
Direct injection
Neoplasm Antigens

Cite this

Williams, Briana Jill ; Bhatia, Shilpa ; Adams, Lisa K. ; Boling, Susan ; Carroll, Jennifer L. ; Li, Xiao Lin ; Rogers, Donna L. ; Korokhov, Nikolay ; Kovesdi, Imre ; Pereboev, Alexander V. ; Curiel, David T. ; Mathis, James Michael. / Dendritic Cell Based PSMA Immunotherapy for Prostate Cancer Using a CD40-Targeted Adenovirus Vector. In: PLoS ONE. 2012 ; Vol. 7, No. 10.
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abstract = "Human prostate tumor vaccine and gene therapy trials using ex vivo methods to prime dendritic cells (DCs) with prostate specific membrane antigen (PSMA) have been somewhat successful, but to date the lengthy ex vivo manipulation of DCs has limited the widespread clinical utility of this approach. Our goal was to improve upon cancer vaccination with tumor antigens by delivering PSMA via a CD40-targeted adenovirus vector directly to DCs as an efficient means for activation and antigen presentation to T-cells. To test this approach, we developed a mouse model of prostate cancer by generating clonal derivatives of the mouse RM-1 prostate cancer cell line expressing human PSMA (RM-1-PSMA cells). To maximize antigen presentation in target cells, both MHC class I and TAP protein expression was induced in RM-1 cells by transduction with an Ad vector expressing interferon-gamma (Ad5-IFNγ). Administering DCs infected ex vivo with CD40-targeted Ad5-huPSMA, as well as direct intraperitoneal injection of the vector, resulted in high levels of tumor-specific CTL responses against RM-1-PSMA cells pretreated with Ad5-IFNγ as target cells. CD40 targeting significantly improved the therapeutic antitumor efficacy of Ad5-huPSMA encoding PSMA when combined with Ad5-IFNγ in the RM-1-PSMA model. These results suggest that a CD-targeted adenovirus delivering PSMA may be effective clinically for prostate cancer immunotherapy.",
author = "Williams, {Briana Jill} and Shilpa Bhatia and Adams, {Lisa K.} and Susan Boling and Carroll, {Jennifer L.} and Li, {Xiao Lin} and Rogers, {Donna L.} and Nikolay Korokhov and Imre Kovesdi and Pereboev, {Alexander V.} and Curiel, {David T.} and Mathis, {James Michael}",
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Williams, BJ, Bhatia, S, Adams, LK, Boling, S, Carroll, JL, Li, XL, Rogers, DL, Korokhov, N, Kovesdi, I, Pereboev, AV, Curiel, DT & Mathis, JM 2012, 'Dendritic Cell Based PSMA Immunotherapy for Prostate Cancer Using a CD40-Targeted Adenovirus Vector', PLoS ONE, vol. 7, no. 10, e46981. https://doi.org/10.1371/journal.pone.0046981

Dendritic Cell Based PSMA Immunotherapy for Prostate Cancer Using a CD40-Targeted Adenovirus Vector. / Williams, Briana Jill; Bhatia, Shilpa; Adams, Lisa K.; Boling, Susan; Carroll, Jennifer L.; Li, Xiao Lin; Rogers, Donna L.; Korokhov, Nikolay; Kovesdi, Imre; Pereboev, Alexander V.; Curiel, David T.; Mathis, James Michael.

In: PLoS ONE, Vol. 7, No. 10, e46981, 08.10.2012.

Research output: Contribution to journalArticleResearchpeer-review

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