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Cancer Therapy: Preclinical

Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression

Maria Parkhurst, Alena Gros, Anna Pasetto, Todd Prickett, Jessica S. Crystal, Paul Robbins and Steven A. Rosenberg
Maria Parkhurst
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  • For correspondence: Maria_Parkhurst@nih.gov
Alena Gros
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Anna Pasetto
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Todd Prickett
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Jessica S. Crystal
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Paul Robbins
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Steven A. Rosenberg
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DOI: 10.1158/1078-0432.CCR-16-2680
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Abstract

Purpose: The adoptive transfer of lymphocytes genetically modified to express tumor reactive T-cell receptors (TCR) can mediate tumor regression. Some tumor-infiltrating lymphocytes (TIL) recognize somatic mutations expressed only in the patient's tumors, and evidence suggests that clinically effective TILs target tumor-specific neoantigens. Here we attempted to isolate neoantigen-reactive TCRs as a prelude to the treatment of patients with autologous T cells genetically modified to express such TCRs.

Experimental Design: Mutations expressed by tumors were identified using whole-exome and RNA sequencing. Tandem minigene (TMG) constructs encoding 12–24 mutated gene products were synthesized, each encoding the mutated amino acid flanked by 12 amino acids of the normal protein sequence. TILs were cultured with autologous dendritic cells (DC) transfected with in vitro transcribed (IVT) mRNAs encoding TMGs and were evaluated for IFNγ secretion and CD137 expression. Neoantigen-reactive T cells were enriched from TILs by sorting for CD137+ CD8+ T cells and expanded in vitro. Dominant TCR α and β chains were identified in the enriched populations using a combination of 5′ rapid amplification of cDNA ends, deep sequencing of genomic DNA, PairSeq analysis, and single-cell RT-PCR analysis. Human PBL retrovirally transduced to express the TCRs were evaluated for recognition of relevant neoantigens.

Results: We identified 27 TCRs from 6 patients that recognized 14 neoantigens expressed by autologous tumor cells.

Conclusions: This strategy provides the means to generate T cells expressing neoantigen-reactive TCRs for use in future adoptive cell transfer immunotherapy trials for patients with cancer. Clin Cancer Res; 1–15. ©2016 AACR.

Footnotes

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

  • Received October 25, 2016.
  • Revision received November 2, 2016.
  • Accepted November 2, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst March 10, 2017
doi: 10.1158/1078-0432.CCR-16-2680

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Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression
Maria Parkhurst, Alena Gros, Anna Pasetto, Todd Prickett, Jessica S. Crystal, Paul Robbins and Steven A. Rosenberg
Clin Cancer Res March 10 2017 DOI: 10.1158/1078-0432.CCR-16-2680

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Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Expression
Maria Parkhurst, Alena Gros, Anna Pasetto, Todd Prickett, Jessica S. Crystal, Paul Robbins and Steven A. Rosenberg
Clin Cancer Res March 10 2017 DOI: 10.1158/1078-0432.CCR-16-2680
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Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

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