Clonal driver neoantigen loss under EGFR TKI and immune selection pressures
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Maise Al Bakir James L Reading Samuel Gamble Rachel Rosenthal Imran Uddin Andrew Rowan Aska (Joanna) Przewrocka Amber Rogers Yien Ning Sophia Wong Amalie K Bentzen Selvaraju Veeriah Sophie Ward Aaron T Garnett Paula Kalavakur Carlos Martínez-Ruiz Clare Puttick Ariana Huebner Daniel E Cook David A Moore Chris Abbosh Crispin Hiley Cristina Naceur-Lombardelli Tom 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 IM Tree Mohammad Kadivar Sine Reker Hadrup Benny Chain Sergio A Quezada Nicholas McGranahan Charles Swanton
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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.
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Journal
Nature
Volume
639
Issue number
8056
Pages
1052-1059
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10.1038/s41586-025-08586-y
Europe PubMed Central
39972134
Pubmed
39972134
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