Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-β Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease

Qiang Zhang*, Brian T. Helfand, Benedito A. Carneiro, Weijun Qin, Ximing J. Yang, Chung Lee, Weipeng Zhang, Francis J. Giles, Massimo Cristofanilli, Timothy Michael Kuzel

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8+ T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-β (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8+ T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene (PZ1) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8+ T-cells to be PSMA reactive and insensitive to TGF-ß. Cr51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8+ T-cells was evaluated using an immunodeficient RAG-1–/– mouse model. We found PSMA-specific, TGF-ß insensitive CD8+ T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8+ T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8+ T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8+ T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. Patient summary: We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-ß insensitive CD8+ T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer. We developed a novel chimeric antigen receptor-T immunotherapy based on prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-ß insensitive CD8+ T-cells derived from metastatic castrate-resistant prostate cancer patient for PSMA-positive prostate cancer. These cells could kill PSMA positive prostate cancer specifically, suggesting it is a potential new approach for mCRPC patients.

Original languageEnglish (US)
Pages (from-to)648-652
Number of pages5
JournalEuropean urology
Volume73
Issue number5
DOIs
StatePublished - May 2018

Keywords

  • CD8 T-cells
  • PSMA
  • Prostate cancer
  • TGF-β
  • mCRPC

ASJC Scopus subject areas

  • Urology

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