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Cancer Discovery
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Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy

Theodore S. Nowicki, Colin Farrell, Marco Morselli, Liudmilla Rubbi, Katie M. Campbell, Mignonette H. Macabali, Beata Berent-Maoz, Begoña Comin-Anduix, Matteo Pellegrini and Antoni Ribas
Theodore S. Nowicki
1Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, California.
2Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California.
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  • For correspondence: tnowicki@mednet.ucla.edu
Colin Farrell
4Department of Human Genetics, University of California, Los Angeles, Los Angeles, California.
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Marco Morselli
5Institute for Quantitative and Computational Biosciences – The Collaboratory, University of California, Los Angeles, Los Angeles, California.
6Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California.
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  • ORCID record for Marco Morselli
Liudmilla Rubbi
6Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California.
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Katie M. Campbell
7Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
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  • ORCID record for Katie M. Campbell
Mignonette H. Macabali
7Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
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Beata Berent-Maoz
7Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
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Begoña Comin-Anduix
2Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
8Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, Los Angeles, California.
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Matteo Pellegrini
2Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
5Institute for Quantitative and Computational Biosciences – The Collaboratory, University of California, Los Angeles, Los Angeles, California.
6Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California.
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Antoni Ribas
2Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
3Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California.
7Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.
8Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, Los Angeles, California.
9Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California.
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DOI: 10.1158/2159-8290.CD-20-0300 Published November 2020
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Abstract

Transgenic T-cell receptor (TCR) adoptive cell therapies recognizing tumor antigens are associated with robust initial response rates, but frequent disease relapse. This usually occurs in the setting of poor long-term persistence of cells expressing the transgenic TCR, generated using murine stem cell virus (MSCV) γ-retroviral vectors. Analysis of clinical transgenic adoptive cell therapy products in vivo revealed that despite strong persistence of the transgenic TCR DNA sequence over time, its expression was profoundly decreased over time at the RNA and protein levels. Patients with the greatest degrees of expression suppression displayed significant increases in DNA methylation over time within the MSCV promoter region, as well as progressive increases in DNA methylation within the entire MSCV vector over time. These increases in vector methylation occurred independently of its integration site within the host genomes. These results have significant implications for the design of future viral vector gene–engineered adoptive cell transfer therapies.

Significance: Cellular immunotherapies' reliance on retroviral vectors encoding foreign genetic material can be vulnerable to progressive acquisition of DNA methylation and subsequent epigenetic suppression of the transgenic product in TCR adoptive cell therapy. This must be considered in the design of future generations of cellular immunotherapies for cancer.

This article is highlighted in the In This Issue feature, p. 1611

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2020;10:1645–53

  • Received March 11, 2020.
  • Revision received May 21, 2020.
  • Accepted July 7, 2020.
  • Published first July 22, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 10 (11)
November 2020
Volume 10, Issue 11
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Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy
Theodore S. Nowicki, Colin Farrell, Marco Morselli, Liudmilla Rubbi, Katie M. Campbell, Mignonette H. Macabali, Beata Berent-Maoz, Begoña Comin-Anduix, Matteo Pellegrini and Antoni Ribas
Cancer Discov November 1 2020 (10) (11) 1645-1653; DOI: 10.1158/2159-8290.CD-20-0300

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Epigenetic Suppression of Transgenic T-cell Receptor Expression via Gamma-Retroviral Vector Methylation in Adoptive Cell Transfer Therapy
Theodore S. Nowicki, Colin Farrell, Marco Morselli, Liudmilla Rubbi, Katie M. Campbell, Mignonette H. Macabali, Beata Berent-Maoz, Begoña Comin-Anduix, Matteo Pellegrini and Antoni Ribas
Cancer Discov November 1 2020 (10) (11) 1645-1653; DOI: 10.1158/2159-8290.CD-20-0300
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