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Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies.
Lo, Amy A; Wallace, Andrew; Oreper, Daniel; Lounsbury, Nicolas; Havnar, Charles; Pechuan-Jorge, Ximo; Wu, Thomas D; Bourgon, Richard; Jones, Ryan; Krogh, Katrina; Yang, Guang-Yu; Zill, Oliver A.
Afiliación
  • Lo AA; Department of Research Pathology, Genentech Inc, South San Francisco, California, USA lo.amy@gene.com oliver@init.bio.
  • Wallace A; Department of Oncology Bioinformatics, Genentech Inc, South San Francisco, California, USA.
  • Oreper D; Department of Oncology Bioinformatics, Genentech Inc, South San Francisco, California, USA.
  • Lounsbury N; Department of Oncology Bioinformatics, Genentech Inc, South San Francisco, California, USA.
  • Havnar C; Department of Research Pathology, Genentech Inc, South San Francisco, California, USA.
  • Pechuan-Jorge X; Department of Cancer Immunology, Genentech Inc, South San Francisco, California, USA.
  • Wu TD; Department of Oncology Bioinformatics, Genentech Inc, South San Francisco, California, USA.
  • Bourgon R; Department of Oncology Bioinformatics, Genentech Inc, South San Francisco, California, USA.
  • Jones R; Department of Pathology, Northwestern University, Chicago, Illinois, USA.
  • Krogh K; Department of Pathology, Northwestern University, Chicago, Illinois, USA.
  • Yang GY; Department of Pathology, Northwestern University, Chicago, Illinois, USA.
  • Zill OA; Department of Oncology Bioinformatics, Genentech Inc, South San Francisco, California, USA lo.amy@gene.com oliver@init.bio.
J Immunother Cancer ; 9(10)2021 10.
Article en En | MEDLINE | ID: mdl-34599029
ABSTRACT

BACKGROUND:

Individualized neoantigen-specific immunotherapy (iNeST) requires robustly expressed clonal neoantigens for efficacy, but tumor mutational heterogeneity, loss of neoantigen expression, and variable tissue sampling present challenges. It is assumed that clonal neoantigens are preferred targets for immunotherapy, but the distributions of clonal neoantigens are not well characterized across cancer types.

METHODS:

We combined multiregion sequencing (MR-seq) analysis of five untreated, synchronously sampled metastatic solid tumors with re-analysis of published MR-seq data from 103 patients in order to characterize their globally clonal neoantigen content and factors that would impact neoantigen targeting.

RESULTS:

Branching evolution in colorectal cancer and renal cell carcinoma led to fewer clonal neoantigens and to clade-specific neoantigens (those shared across a subset of tumor regions but not fully clonal), with the latter not being readily distinguishable in single tumor samples. In colorectal, renal, and bladder cancer, most tumors had few globally clonal neoantigens. Prioritizing mutations with higher purity-adjusted and ploidy-adjusted variant allele frequency enriched for globally clonal neoantigens (those found in all tumor regions), whereas estimated cancer cell fraction derived from clustering-based tools, surprisingly, did not. Neoantigen quality was associated with loss of neoantigen expression in the bladder cancer case, and HLA-allele loss was observed in the renal and non-small cell lung cancer cases.

CONCLUSIONS:

We show that tumor type, multilesion sampling, neoantigen expression, and HLA allele retention are important factors for iNeST targeting and patient selection, and may also be important factors to consider in the development of biomarker strategies.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Biomarcadores de Tumor / Inmunoterapia / Antígenos de Neoplasias / Neoplasias Límite: Adult / Aged / Aged80 / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Immunother Cancer Año: 2021 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Biomarcadores de Tumor / Inmunoterapia / Antígenos de Neoplasias / Neoplasias Límite: Adult / Aged / Aged80 / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Immunother Cancer Año: 2021 Tipo del documento: Article