A novel murine T-cell receptor targeting NY-ESO-1

Shannon F. Rosati, Maria R. Parkhurst, Young Hong, Zhili Zheng, Steven A. Feldman, Mahadev Rao, Daniel Abate-Daga, Rachel E. Beard, Hui Xu, Mary A. Black, Paul F. Robbins, David A. Schrump, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Cancer testis antigens, such as NY-ESO-1, are expressed in a variety of prevalent tumors and represent potential targets for T-cell receptor (TCR) gene therapy. DNA encoding a murine anti-NY-ESO-1 TCR gene (mTCR) was isolated from immunized HLA-A*0201 transgenic mice and inserted into a γ-retroviral vector. Two mTCR vectors were produced and used to transduce human PBL. Transduced cells were cocultured with tumor target cell lines and T2 cells pulsed with the NY-ESO-1 peptide, and assayed for cytokine release and cell lysis activity. The most active TCR construct was selected for production of a master cell bank for clinical use. mTCR-transduced PBL maintained TCR expression in short-term and long-term culture, ranging from 50% to 90% efficiency 7-11 days after stimulation and 46%-82% 10-20 days after restimulation. High levels of interferon-γ secretion were observed (1000-12000 pg/mL), in tumor coculture assays and recognition of peptide-pulsed cells was observed at 0.1 ng/mL, suggesting that the new mTCR had high avidity for antigen recognition. mTCR-transduced T cells also specifically lysed human tumor targets. In all assays, the mTCR was equivalent or better than the comparable human TCR. As the functional activity of TCR-transduced cells may be affected by the formation of mixed dimers, mTCRs, which are less likely to form mixed dimers with endogenous hTCRs, may be more effective in vivo. This new mTCR targeted to NY-ESO-1 represents a novel potential therapeutic option for adoptive cell-transfer therapy for a variety of malignancies.

Original languageEnglish
Pages (from-to)135-146
Number of pages12
JournalJournal of Immunotherapy
Volume37
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

T-Cell Antigen Receptor
T-Cell Receptor Genes
Neoplasms
Antigens
Peptides
Adoptive Transfer
Testicular Neoplasms
Cell- and Tissue-Based Therapy
Coculture Techniques
Tumor Cell Line
Genetic Therapy
Interferons
Transgenic Mice
Cytokines
T-Lymphocytes
DNA

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

Cite this

Rosati, S. F., Parkhurst, M. R., Hong, Y., Zheng, Z., Feldman, S. A., Rao, M., ... Morgan, R. A. (2014). A novel murine T-cell receptor targeting NY-ESO-1. Journal of Immunotherapy, 37(3), 135-146. https://doi.org/10.1097/CJI.0000000000000019
Rosati, Shannon F. ; Parkhurst, Maria R. ; Hong, Young ; Zheng, Zhili ; Feldman, Steven A. ; Rao, Mahadev ; Abate-Daga, Daniel ; Beard, Rachel E. ; Xu, Hui ; Black, Mary A. ; Robbins, Paul F. ; Schrump, David A. ; Rosenberg, Steven A. ; Morgan, Richard A. / A novel murine T-cell receptor targeting NY-ESO-1. In: Journal of Immunotherapy. 2014 ; Vol. 37, No. 3. pp. 135-146.
@article{08cdf96772a54321831a2fad16d763cf,
title = "A novel murine T-cell receptor targeting NY-ESO-1",
abstract = "Cancer testis antigens, such as NY-ESO-1, are expressed in a variety of prevalent tumors and represent potential targets for T-cell receptor (TCR) gene therapy. DNA encoding a murine anti-NY-ESO-1 TCR gene (mTCR) was isolated from immunized HLA-A*0201 transgenic mice and inserted into a γ-retroviral vector. Two mTCR vectors were produced and used to transduce human PBL. Transduced cells were cocultured with tumor target cell lines and T2 cells pulsed with the NY-ESO-1 peptide, and assayed for cytokine release and cell lysis activity. The most active TCR construct was selected for production of a master cell bank for clinical use. mTCR-transduced PBL maintained TCR expression in short-term and long-term culture, ranging from 50{\%} to 90{\%} efficiency 7-11 days after stimulation and 46{\%}-82{\%} 10-20 days after restimulation. High levels of interferon-γ secretion were observed (1000-12000 pg/mL), in tumor coculture assays and recognition of peptide-pulsed cells was observed at 0.1 ng/mL, suggesting that the new mTCR had high avidity for antigen recognition. mTCR-transduced T cells also specifically lysed human tumor targets. In all assays, the mTCR was equivalent or better than the comparable human TCR. As the functional activity of TCR-transduced cells may be affected by the formation of mixed dimers, mTCRs, which are less likely to form mixed dimers with endogenous hTCRs, may be more effective in vivo. This new mTCR targeted to NY-ESO-1 represents a novel potential therapeutic option for adoptive cell-transfer therapy for a variety of malignancies.",
author = "Rosati, {Shannon F.} and Parkhurst, {Maria R.} and Young Hong and Zhili Zheng and Feldman, {Steven A.} and Mahadev Rao and Daniel Abate-Daga and Beard, {Rachel E.} and Hui Xu and Black, {Mary A.} and Robbins, {Paul F.} and Schrump, {David A.} and Rosenberg, {Steven A.} and Morgan, {Richard A.}",
year = "2014",
doi = "10.1097/CJI.0000000000000019",
language = "English",
volume = "37",
pages = "135--146",
journal = "Journal of Immunotherapy",
issn = "1524-9557",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

Rosati, SF, Parkhurst, MR, Hong, Y, Zheng, Z, Feldman, SA, Rao, M, Abate-Daga, D, Beard, RE, Xu, H, Black, MA, Robbins, PF, Schrump, DA, Rosenberg, SA & Morgan, RA 2014, 'A novel murine T-cell receptor targeting NY-ESO-1', Journal of Immunotherapy, vol. 37, no. 3, pp. 135-146. https://doi.org/10.1097/CJI.0000000000000019

A novel murine T-cell receptor targeting NY-ESO-1. / Rosati, Shannon F.; Parkhurst, Maria R.; Hong, Young; Zheng, Zhili; Feldman, Steven A.; Rao, Mahadev; Abate-Daga, Daniel; Beard, Rachel E.; Xu, Hui; Black, Mary A.; Robbins, Paul F.; Schrump, David A.; Rosenberg, Steven A.; Morgan, Richard A.

In: Journal of Immunotherapy, Vol. 37, No. 3, 2014, p. 135-146.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel murine T-cell receptor targeting NY-ESO-1

AU - Rosati, Shannon F.

AU - Parkhurst, Maria R.

AU - Hong, Young

AU - Zheng, Zhili

AU - Feldman, Steven A.

AU - Rao, Mahadev

AU - Abate-Daga, Daniel

AU - Beard, Rachel E.

AU - Xu, Hui

AU - Black, Mary A.

AU - Robbins, Paul F.

AU - Schrump, David A.

AU - Rosenberg, Steven A.

AU - Morgan, Richard A.

PY - 2014

Y1 - 2014

N2 - Cancer testis antigens, such as NY-ESO-1, are expressed in a variety of prevalent tumors and represent potential targets for T-cell receptor (TCR) gene therapy. DNA encoding a murine anti-NY-ESO-1 TCR gene (mTCR) was isolated from immunized HLA-A*0201 transgenic mice and inserted into a γ-retroviral vector. Two mTCR vectors were produced and used to transduce human PBL. Transduced cells were cocultured with tumor target cell lines and T2 cells pulsed with the NY-ESO-1 peptide, and assayed for cytokine release and cell lysis activity. The most active TCR construct was selected for production of a master cell bank for clinical use. mTCR-transduced PBL maintained TCR expression in short-term and long-term culture, ranging from 50% to 90% efficiency 7-11 days after stimulation and 46%-82% 10-20 days after restimulation. High levels of interferon-γ secretion were observed (1000-12000 pg/mL), in tumor coculture assays and recognition of peptide-pulsed cells was observed at 0.1 ng/mL, suggesting that the new mTCR had high avidity for antigen recognition. mTCR-transduced T cells also specifically lysed human tumor targets. In all assays, the mTCR was equivalent or better than the comparable human TCR. As the functional activity of TCR-transduced cells may be affected by the formation of mixed dimers, mTCRs, which are less likely to form mixed dimers with endogenous hTCRs, may be more effective in vivo. This new mTCR targeted to NY-ESO-1 represents a novel potential therapeutic option for adoptive cell-transfer therapy for a variety of malignancies.

AB - Cancer testis antigens, such as NY-ESO-1, are expressed in a variety of prevalent tumors and represent potential targets for T-cell receptor (TCR) gene therapy. DNA encoding a murine anti-NY-ESO-1 TCR gene (mTCR) was isolated from immunized HLA-A*0201 transgenic mice and inserted into a γ-retroviral vector. Two mTCR vectors were produced and used to transduce human PBL. Transduced cells were cocultured with tumor target cell lines and T2 cells pulsed with the NY-ESO-1 peptide, and assayed for cytokine release and cell lysis activity. The most active TCR construct was selected for production of a master cell bank for clinical use. mTCR-transduced PBL maintained TCR expression in short-term and long-term culture, ranging from 50% to 90% efficiency 7-11 days after stimulation and 46%-82% 10-20 days after restimulation. High levels of interferon-γ secretion were observed (1000-12000 pg/mL), in tumor coculture assays and recognition of peptide-pulsed cells was observed at 0.1 ng/mL, suggesting that the new mTCR had high avidity for antigen recognition. mTCR-transduced T cells also specifically lysed human tumor targets. In all assays, the mTCR was equivalent or better than the comparable human TCR. As the functional activity of TCR-transduced cells may be affected by the formation of mixed dimers, mTCRs, which are less likely to form mixed dimers with endogenous hTCRs, may be more effective in vivo. This new mTCR targeted to NY-ESO-1 represents a novel potential therapeutic option for adoptive cell-transfer therapy for a variety of malignancies.

UR - http://www.scopus.com/inward/record.url?scp=84896398249&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896398249&partnerID=8YFLogxK

U2 - 10.1097/CJI.0000000000000019

DO - 10.1097/CJI.0000000000000019

M3 - Article

VL - 37

SP - 135

EP - 146

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

SN - 1524-9557

IS - 3

ER -

Rosati SF, Parkhurst MR, Hong Y, Zheng Z, Feldman SA, Rao M et al. A novel murine T-cell receptor targeting NY-ESO-1. Journal of Immunotherapy. 2014;37(3):135-146. https://doi.org/10.1097/CJI.0000000000000019