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Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report

Clinical trials of chimeric antigen receptor (CAR) T cells in hematologic malignancy associate remissions with two profiles of CAR T cell proliferation kinetics, which differ based upon costimulatory domain. Additional T cell intrinsic factors that influence or predict clinical response remain uncle...

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Autores principales: Funk, Christopher Ronald, Petersen, Christopher T., Jagirdar, Neera, Ravindranathan, Sruthi, Jaye, David L., Flowers, Christopher R., Langston, Amelia, Waller, Edmund K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320786/
https://www.ncbi.nlm.nih.gov/pubmed/30572564
http://dx.doi.org/10.3390/ijms19124118
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author Funk, Christopher Ronald
Petersen, Christopher T.
Jagirdar, Neera
Ravindranathan, Sruthi
Jaye, David L.
Flowers, Christopher R.
Langston, Amelia
Waller, Edmund K.
author_facet Funk, Christopher Ronald
Petersen, Christopher T.
Jagirdar, Neera
Ravindranathan, Sruthi
Jaye, David L.
Flowers, Christopher R.
Langston, Amelia
Waller, Edmund K.
author_sort Funk, Christopher Ronald
collection PubMed
description Clinical trials of chimeric antigen receptor (CAR) T cells in hematologic malignancy associate remissions with two profiles of CAR T cell proliferation kinetics, which differ based upon costimulatory domain. Additional T cell intrinsic factors that influence or predict clinical response remain unclear. To address this gap, we report the case of a 68-year-old woman with refractory/relapsed diffuse large B cell lymphoma (DLBCL), treated with tisagenlecleucel (anti-CD19), with a CD137 costimulatory domain (4-1BB) on an investigational new drug application (#16944). For two months post-infusion, the patient experienced dramatic regression of subcutaneous nodules of DLBCL. Unfortunately, her CAR T exhibited kinetics unassociated with remission, and she died of DLBCL-related sequelae. Serial phenotypic analysis of peripheral blood alongside sequencing of the β-peptide variable region of the T cell receptor (TCRβ) revealed distinct waves of oligoclonal T cell expansion with dynamic expression of immune checkpoint molecules. One week prior to CAR T cell contraction, T cell immunoglobulin mucin domain 3 (Tim-3) and programmed cell death protein 1 (PD-1) exhibited peak expressions on both the CD8 T cell (Tim-3 ≈ 50%; PD-1 ≈ 17%) and CAR T cell subsets (Tim-3 ≈ 78%; PD-1 ≈ 40%). These correlative observations draw attention to Tim-3 and PD-1 signaling pathways in context of CAR T cell exhaustion.
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spelling pubmed-63207862019-01-07 Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report Funk, Christopher Ronald Petersen, Christopher T. Jagirdar, Neera Ravindranathan, Sruthi Jaye, David L. Flowers, Christopher R. Langston, Amelia Waller, Edmund K. Int J Mol Sci Case Report Clinical trials of chimeric antigen receptor (CAR) T cells in hematologic malignancy associate remissions with two profiles of CAR T cell proliferation kinetics, which differ based upon costimulatory domain. Additional T cell intrinsic factors that influence or predict clinical response remain unclear. To address this gap, we report the case of a 68-year-old woman with refractory/relapsed diffuse large B cell lymphoma (DLBCL), treated with tisagenlecleucel (anti-CD19), with a CD137 costimulatory domain (4-1BB) on an investigational new drug application (#16944). For two months post-infusion, the patient experienced dramatic regression of subcutaneous nodules of DLBCL. Unfortunately, her CAR T exhibited kinetics unassociated with remission, and she died of DLBCL-related sequelae. Serial phenotypic analysis of peripheral blood alongside sequencing of the β-peptide variable region of the T cell receptor (TCRβ) revealed distinct waves of oligoclonal T cell expansion with dynamic expression of immune checkpoint molecules. One week prior to CAR T cell contraction, T cell immunoglobulin mucin domain 3 (Tim-3) and programmed cell death protein 1 (PD-1) exhibited peak expressions on both the CD8 T cell (Tim-3 ≈ 50%; PD-1 ≈ 17%) and CAR T cell subsets (Tim-3 ≈ 78%; PD-1 ≈ 40%). These correlative observations draw attention to Tim-3 and PD-1 signaling pathways in context of CAR T cell exhaustion. MDPI 2018-12-19 /pmc/articles/PMC6320786/ /pubmed/30572564 http://dx.doi.org/10.3390/ijms19124118 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Funk, Christopher Ronald
Petersen, Christopher T.
Jagirdar, Neera
Ravindranathan, Sruthi
Jaye, David L.
Flowers, Christopher R.
Langston, Amelia
Waller, Edmund K.
Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report
title Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report
title_full Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report
title_fullStr Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report
title_full_unstemmed Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report
title_short Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report
title_sort oligoclonal t cells transiently expand and express tim-3 and pd-1 following anti-cd19 car t cell therapy: a case report
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320786/
https://www.ncbi.nlm.nih.gov/pubmed/30572564
http://dx.doi.org/10.3390/ijms19124118
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