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

Cancer Discovery
Theodore S NowickiAntoni Ribas

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 subsequ...Continue Reading

References

Feb 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alexander PfeiferInder M Verma
Nov 9, 2002·Bioinformatics·Long-Cheng Li, Rajvir Dahiya
Jul 6, 2004·Molecular Therapy : the Journal of the American Society of Gene Therapy·Shuyuan YaoJames Ellis
Mar 11, 2005·Proceedings of the National Academy of Sciences of the United States of America·Lili Yang, David Baltimore
Jan 7, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Begoña Comin-AnduixAntoni Ribas
May 2, 2006·Molecular Therapy : the Journal of the American Society of Gene Therapy·Mari AkerDavid W Emery
Sep 2, 2006·Science·Richard A MorganSteven A Rosenberg
May 20, 2008·Nucleic Acids Research·Yuichi KumakiMasaki Okano
Jun 21, 2008·The New England Journal of Medicine·Naomi N HunderCassian Yee
Jun 10, 2009·Bioinformatics·Heng LiUNKNOWN 1000 Genome Project Data Processing Subgroup
Nov 30, 2011·Proceedings of the National Academy of Sciences of the United States of America·Dimitrios N VatakisJerome A Zack
Feb 7, 2012·Journal of Immunotherapy·Jeffrey ChouEdus H Warren
Oct 26, 2013·Nature Communications·Christopher S CarlsonHarlan Robins
Feb 7, 2014·Journal of Virology·Suk See De RavinXiaolin Wu
Mar 19, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Thinle ChodonAntoni Ribas
Dec 30, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Paul F RobbinsSteven A Rosenberg
Mar 1, 2016·Advances in Immunology·James C Yang, Steven A Rosenberg
Jul 5, 2018·The New England Journal of Medicine·Carl H June, Michel Sadelain
Dec 24, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Theodore S NowickiAntoni Ribas
Jun 8, 2019·Molecular Genetics & Genomic Medicine·Yingyun FuYong Dai
Jul 31, 2019·Nature Medicine·Kathryn E YostHoward Y Chang

❮ Previous
Next ❯

Citations

Jun 9, 2021·Signal Transduction and Targeted Therapy·Li ChenZhiyao He
Nov 4, 2021·Cancer Immunology Research·Uri GreenbaumDavid S Hong
Sep 29, 2021·Journal of the National Cancer Institute·Carlos A Garcia-PrietoManel Esteller

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Biology: Molecular Imaging

Molecular imaging enables noninvasive imaging of key molecules that are crucial to tumor biology. Discover the latest research in molecular imaging in cancer biology in this feed.