Targeting human melanoma neoantigens by T cell receptor gene therapy

The Journal of Clinical Investigation
Matthias LeisegangThomas Blankenstein

Abstract

In successful cancer immunotherapy, T cell responses appear to be directed toward neoantigens created by somatic mutations; however, direct evidence that neoantigen-specific T cells cause regression of established cancer is lacking. Here, we generated T cells expressing a mutation-specific transgenic T cell receptor (TCR) to target different immunogenic mutations in cyclin-dependent kinase 4 (CDK4) that naturally occur in human melanoma. Two mutant CDK4 isoforms (R24C, R24L) similarly stimulated T cell responses in vitro and were analyzed as therapeutic targets for TCR gene therapy. In a syngeneic HLA-A2-transgenic mouse model of large established tumors, we found that both mutations differed dramatically as targets for TCR-modified T cells in vivo. While T cells expanded efficiently and produced IFN-γ in response to R24L, R24C failed to induce an effective antitumor response. Such differences in neoantigen quality might explain why cancer immunotherapy induces tumor regression in some individuals, while others do not respond, despite similar mutational load. We confirmed the validity of the in vivo model by showing that the melan-A-specific (MART-1-specific) TCR DMF5 induces rejection of tumors expressing analog, but not nativ...Continue Reading

References

Jul 27, 1999·International Journal of Cancer. Journal International Du Cancer·J C SkipperC L Slingluff
Nov 24, 1999·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M B AtkinsS A Rosenberg
Feb 26, 2004·Nature Medicine·Michael T SpiottoHans Schreiber
Mar 16, 2005·Current Opinion in Immunology·Thomas Blankenstein
Sep 2, 2005·Nature·Gerald Willimsky, Thomas Blankenstein
Sep 16, 2008·Molecular Cancer Therapeutics·Keiran S M SmalleyKatherine L Nathanson
Jul 29, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Oleg Y BorbulevychBrian M Baker
Jul 4, 2012·Oncoimmunology·Pia KvistborgTon N M Schumacher
Sep 18, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Nienke van RooijTon N Schumacher
Jun 5, 2014·Cancer Immunology Research·Edward F FritschCatherine J Wu
Aug 2, 2014·Oncoimmunology·Marit M van BuurenTon Nm Schumacher
Nov 28, 2014·Nature·Matthew M GubinRobert D Schreiber
Mar 3, 2015·Current Opinion in Immunology·Thomas BlankensteinHans Schreiber

❮ Previous
Next ❯

Citations

Mar 22, 2016·Seminars in Immunology·Reno DebetsGeorge Coukos
Nov 12, 2016·Cancer Gene Therapy·D D GeorgeS C Katz
Apr 8, 2016·Nature Biotechnology·Thomas Blankenstein
May 16, 2019·European Journal of Immunology·Florian MaduraAndrew K Sewell
Jul 30, 2019·Immunological Reviews·Smita S Chandran, Christopher A Klebanoff
Oct 7, 2017·Current Opinion in Neurology·Iris MildenbergerMichael Platten
Feb 25, 2020·Scandinavian Journal of Immunology·Minjun MaLan Wang
Feb 6, 2020·Annual Review of Immunology·Michael L FrisoliJohn E Harris
Jan 10, 2018·Frontiers in Immunology·Thomas C Wirth, Florian Kühnel
Dec 31, 2017·Cancer Science·Kazuma KiyotaniYusuke Nakamura
Apr 24, 2016·Journal of Leukocyte Biology·Andrew J ParkWilliam R Levis
May 26, 2018·Bone Marrow Transplantation·Fred FalkenburgHans Jochem Kolb
Dec 12, 2018·The Journal of Clinical Investigation·Lucia PoncetteThomas Blankenstein
Dec 14, 2019·Cancer Immunology Research·Karin SchreiberMatthias Leisegang
May 4, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Tatsuo MatsudaYusuke Nakamura
Apr 20, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ioannis GavvovidisThomas Blankenstein
Jul 2, 2021·Journal of Human Genetics·Kazuma KiyotaniYusuke Nakamura
Oct 9, 2021·Journal of Internal Medicine·Luca MazzarellaMats Jerkeman

❮ Previous
Next ❯

Related Concepts

Related Feeds

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Cancer Vaccines

Cancer vaccines are vaccines that either treat existing cancer or prevent development of a cancer.