Clonal driver neoantigen loss under EGFR TKI and immune selection pressures

Maise Al Bakir, James L. Reading, Samuel Gamble, Rachel Rosenthal, Imran Uddin, Andrew Rowan, Joanna Przewrocka, Amber Rogers, Yien Ning Sophia Wong, Amalie K. Bentzen, Selvaraju Veeriah, Sophia Ward, Aaron T. Garnett, Paula Kalavakur, Carlos Martínez-Ruiz, Clare Puttick, Ariana Huebner, Daniel E. Cook, David A. Moore, Chris Abbosh, Crispin T. Hiley, Cristina Naceur-Lombardelli, Thomas B. K. Watkins, Marina Petkovic, Roland F. Schwarz, Felipe Gálvez-Cancino, Kevin Litchfield, Peter Meldgaard, Boe Sandahl Sorensen, Line Bille Madsen, Dirk Jäger, Martin D. Forster, Tobias Arkenau, Clara Domingo-Vila, Timothy I. M. Tree, Mohammad Kadivar, Sine Reker Hadrup, Benny Chain, Sergio A. Quezada (), Nicholas McGranahan () and Charles Swanton ()
Additional contact information
Maise Al Bakir: The Francis Crick Institute
James L. Reading: University College London Cancer Institute
Samuel Gamble: University College London Cancer Institute
Rachel Rosenthal: The Francis Crick Institute
Imran Uddin: University College London
Andrew Rowan: The Francis Crick Institute
Joanna Przewrocka: The Francis Crick Institute
Amber Rogers: University College London Cancer Institute
Yien Ning Sophia Wong: University College London Cancer Institute
Amalie K. Bentzen: University College London Cancer Institute
Selvaraju Veeriah: University College London Cancer Institute
Sophia Ward: The Francis Crick Institute
Aaron T. Garnett: Invitae Inc.
Paula Kalavakur: Invitae Inc.
Carlos Martínez-Ruiz: University College London
Clare Puttick: The Francis Crick Institute
Ariana Huebner: The Francis Crick Institute
Daniel E. Cook: The Francis Crick Institute
David A. Moore: The Francis Crick Institute
Chris Abbosh: University College London Cancer Institute
Crispin T. Hiley: The Francis Crick Institute
Cristina Naceur-Lombardelli: University College London Cancer Institute
Thomas B. K. Watkins: The Francis Crick Institute
Marina Petkovic: Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Roland F. Schwarz: University of Cologne
Felipe Gálvez-Cancino: University of Oxford
Kevin Litchfield: The Francis Crick Institute
Peter Meldgaard: Aarhus University Hospital
Boe Sandahl Sorensen: Aarhus University Hospital
Line Bille Madsen: Aarhus University Hospital
Dirk Jäger: Heidelberg University Hospital
Martin D. Forster: University College London Cancer Institute
Tobias Arkenau: Sarah Cannon Research Institute
Clara Domingo-Vila: King’s College London
Timothy I. M. Tree: King’s College London
Mohammad Kadivar: Technical University of Denmark
Sine Reker Hadrup: Technical University of Denmark
Benny Chain: University College London
Sergio A. Quezada: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute
Charles Swanton: The Francis Crick Institute

Nature, 2025, vol. 639, issue 8056, 1052-1059

Abstract: Abstract Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1,2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08586-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:639:y:2025:i:8056:d:10.1038_s41586-025-08586-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08586-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().