About this item:

62 Views | 51 Downloads

Author Notes:

Correspondence: ewaller@emory.edu; Tel.: +1-404-727-4995

C.R.Funk and C.T.P. contributed equally to this work.

C.R.Funk analyzed the data and wrote the manuscript.

C.T.P. collected data.

N.J. collected data.

S.R. analyzed data and edited the manuscript.

D.L.J. collected data and edited the manuscript.

C.R.Flowers, A.L., and E.K.W. each provided clinical care to the patient and edited the manuscript.

E.K.W. conceptualized the study design and provided research funding.

The authors thank the patient and her family for allowing us to study her response to therapy.

The authors declare no conflict of interest.

Subjects:

Research Funding:

C.R.F. is supported by a Howard Hughes Medical Research Fellowship.

The work was supported by Abraham J. and Phyllis Katz Foundation Award 00034291 (E.K.W.).

This work was partially funded from Emory University’s Open Access Publishing Fund.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Physical Sciences
  • Biochemistry & Molecular Biology
  • Chemistry, Multidisciplinary
  • Chemistry
  • CTL019
  • tisagenlecleucel
  • oligoclonal T cell expansion
  • DLBCL
  • T cell immunoglobulin mucin domain 3 (Tim-3)
  • programmed cell death protein 1 (PD-1)

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

Tools:

Journal Title:

International Journal of Molecular Sciences

Volume:

Volume 19, Number 12

Publisher:

Type of Work:

Article | Final Publisher PDF

Abstract:

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.

Copyright information:

© 2018 by the authors. Licensee MDPI, Basel, Switzerland.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote