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Molecular Cancer Research
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Tumor Microenvironment and Immunobiology

A New Pipeline to Predict and Confirm Tumor Neoantigens Predict Better Response to Immune Checkpoint Blockade

Yelena Lazdun, Han Si, Todd Creasy, Koustubh Ranade, Brandon W. Higgs, Katie Streicher and Nicholas M. Durham
Yelena Lazdun
1Translational Functional Genomics, AstraZeneca, Gaithersburg, Maryland.
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  • ORCID record for Yelena Lazdun
Han Si
2Translational Bioinformatics, AstraZeneca, Gaithersburg, Maryland.
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Todd Creasy
2Translational Bioinformatics, AstraZeneca, Gaithersburg, Maryland.
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Koustubh Ranade
3Translational Medicine, Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
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Brandon W. Higgs
2Translational Bioinformatics, AstraZeneca, Gaithersburg, Maryland.
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Katie Streicher
3Translational Medicine, Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
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Nicholas M. Durham
1Translational Functional Genomics, AstraZeneca, Gaithersburg, Maryland.
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  • For correspondence: nicholas.durham@astrazeneca.com
DOI: 10.1158/1541-7786.MCR-19-1118
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Abstract

Mutations that drive oncogenesis in cancer can generate neoantigens that may be recognized by the immune system. Identification of these neoantigens remains challenging due to the complexity of the MHC antigen and T-cell receptor interaction. Here, we describe the development of a systematic approach to efficiently identify and validate immunogenic neoantigens. Whole-exome sequencing of tissue from a patient with melanoma was used to identify nonsynonymous mutations, followed by MHC binding prediction and identification of tumor clonal architecture. The top 18 putative class I neoantigens were selected for immunogenicity testing via a novel in vitro pipeline in HLA-A201 healthy donor blood. Naïve CD8 T cells from donors were stimulated with allogeneic dendritic cells pulsed with peptide pools and then with individual peptides. The presence of antigen-specific T cells was determined via functional assays. We identified one putative neoantigen that expanded T cells specific to the mutant form of the peptide and validated this pipeline in a subset of patients with bladder tumors treated with durvalumab (n = 5). Within this cohort, the top predicted neoantigens from all patients were immunogenic in vitro. Finally, we looked at overall survival in the whole durvalumab-treated bladder cohort (N = 37) by stratifying patients by tertile measure of tumor mutation burden (TMB) or neoantigen load. Patients with higher neoantigen and TMB load tended to show better overall survival.

Implications: This pipeline can enable accurate and rapid identification of personalized neoantigens that may help to identify patients who will survive longer on durvalumab.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;XX:XX–XX

  • Received November 20, 2019.
  • Revision received June 4, 2020.
  • Accepted November 20, 2020.
  • Published first November 30, 2020.
  • ©2020 American Association for Cancer Research.

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This OnlineFirst version was published on January 14, 2021
doi: 10.1158/1541-7786.MCR-19-1118

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A New Pipeline to Predict and Confirm Tumor Neoantigens Predict Better Response to Immune Checkpoint Blockade
Yelena Lazdun, Han Si, Todd Creasy, Koustubh Ranade, Brandon W. Higgs, Katie Streicher and Nicholas M. Durham
Mol Cancer Res January 14 2021 DOI: 10.1158/1541-7786.MCR-19-1118

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A New Pipeline to Predict and Confirm Tumor Neoantigens Predict Better Response to Immune Checkpoint Blockade
Yelena Lazdun, Han Si, Todd Creasy, Koustubh Ranade, Brandon W. Higgs, Katie Streicher and Nicholas M. Durham
Mol Cancer Res January 14 2021 DOI: 10.1158/1541-7786.MCR-19-1118
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Molecular Cancer Research
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