Bakir and Reading et al. reported the loss of an EGFR ex19del driver mutation in a patient treated with osimertinib and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR ex19del. The ex19del mutation, which likely appeared after a whole-genome doubling (WGD) event, was lost in progressing liver metastasis. The liver metastasis exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9, and elevated M2 macrophages. High-resolution ctDNA phylogenetic analyses revealed the wild-type EGFR clones and the neoantigen landscape before vaccination, and their trajectory during osimertinib/NPV therapy.
Contributed by Shishir Pant
ABSTRACT: Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers(1,2). 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 cohort(3) 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.
Author Info: (1) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Canc
Author Info: (1) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (2) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Pre-Cancer Immunology Laboratory, Research Department of Haematology, University College London Cancer Institute, London, UK. (3) Pre-Cancer Immunology Laboratory, Research Department of Haematology, University College London Cancer Institute, London, UK. (4) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (5) Division of Infection and Immunity, University College London, London, UK. (6) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (7) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (8) Pre-Cancer Immunology Laboratory, Research Department of Haematology, University College London Cancer Institute, London, UK. (9) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (10) Pre-Cancer Immunology Laboratory, Research Department of Haematology, University College London Cancer Institute, London, UK. (11) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (12) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Genomics Science Technology Platform, The Francis Crick Institute, London, UK. (13) Invitae Inc., Boulder, CO, USA. (14) Invitae Inc., Boulder, CO, USA. (15) Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. (16) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. (17) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. (18) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (19) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Department of Cellular Pathology, University College London Hospital NHS Foundation Trust, London, UK. (20) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (21) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (22) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (23) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (24) Berlin Institute for Medical Systems Biology, Max Delbrck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. Department of Biology, Humboldt University of Berlin, Berlin, Germany. Division of Oncology and Hematology, Department of Pediatrics, Charit - Universittsmedizin Berlin, Corporate Member of Freie Universitt Berlin and Humboldt Universitt zu Berlin, Berlin, Germany. (25) Institute for Computational Cancer Biology (ICCB), Center for Integrated Oncology (CIO), Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. Berlin Institute for the Foundations of Learning and Data (BIFOLD), Berlin, Germany. (26) Immune-Regulation and Immune-Interactions Laboratory, Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Headington, UK. (27) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (28) Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. (29) Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. (30) Department of Pathology, Aarhus University Hospital, Aarhus, Denmark. (31) Department of Medical Oncology, National Center for Tumor Diseases Heidelberg, Heidelberg University Hospital, Heidelberg, Germany. (32) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Department of Oncology, UCL Cancer Institute, London, UK. (33) Sarah Cannon Research Institute, London, UK. (34) Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK. (35) Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London, UK. (36) Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. (37) Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. (38) Division of Infection and Immunity, University College London, London, UK. Department of Computer Sciences, University College London, London, UK. (39) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. s.quezada@ucl.ac.uk. Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. s.quezada@ucl.ac.uk. (40) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. nicholas.mcgranahan.10@ucl.ac.uk. Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. nicholas.mcgranahan.10@ucl.ac.uk. (41) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. charles.swanton@crick.ac.uk. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. charles.swanton@crick.ac.uk.
