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 M. Kuzel

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 1 2018

Fingerprint

Transforming Growth Factors
Prostatic Neoplasms
T-Lymphocytes
Immunotherapy
Antigen Receptors
human glutamate carboxypeptidase II
Thymidine Kinase
Immunosuppressive Agents
Neoplasms
T-Cell Antigen Receptor Specificity
Leukapheresis
T-Cell Receptor Genes
Ganciclovir
Tumor Microenvironment
Growth Factor Receptors
Human Herpesvirus 1
Financial Management
United States Food and Drug Administration
Therapeutics
T-Cell Antigen Receptor

Keywords

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

ASJC Scopus subject areas

  • Urology

Cite this

@article{6c744c657d484f2a9d8243337c52b430,
title = "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",
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 (T{\ss}RIIDN), 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.",
keywords = "CD8 T-cells, PSMA, Prostate cancer, TGF-β, mCRPC",
author = "Qiang Zhang and Helfand, {Brian T.} and Carneiro, {Benedito A.} and Weijun Qin and Yang, {Ximing J} and Chung Lee and Weipeng Zhang and Giles, {Francis J.} and Massimo Cristofanilli and Kuzel, {Timothy M.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1016/j.eururo.2017.12.008",
language = "English (US)",
volume = "73",
pages = "648--652",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",
number = "5",

}

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

In: European Urology, Vol. 73, No. 5, 01.05.2018, p. 648-652.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Zhang, Qiang

AU - Helfand, Brian T.

AU - Carneiro, Benedito A.

AU - Qin, Weijun

AU - Yang, Ximing J

AU - Lee, Chung

AU - Zhang, Weipeng

AU - Giles, Francis J.

AU - Cristofanilli, Massimo

AU - Kuzel, Timothy M.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

KW - CD8 T-cells

KW - PSMA

KW - Prostate cancer

KW - TGF-β

KW - mCRPC

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