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

• Type of Material: Article
• Authors: Christopher Ronald Funk, Emory University; Christopher T. Petersen, Emory University; Neera Jagirdar, Emory University; Sruthi Ravindranathan, Emory University; David L Jaye, Emory University; Christopher R Flowers, Emory University; Amelia Langston, Emory University; Edmund K Waller, Emory University
• Language: English
• Date: 2018-12-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2018 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms19124118
• Title of Journal or Parent Work: International Journal of Molecular Sciences
• ISSN: 1661-6596
• Volume: 19
• Issue: 12
• Grant/Funding Information: 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: Life Sciences & Biomedicine; tisagenlecleucel; Chemistry, Multidisciplinary; DLBCL; programmed cell death protein 1 (PD-1); oligoclonal T cell expansion; Physical Sciences; T cell immunoglobulin mucin domain 3 (Tim-3); Biochemistry & Molecular Biology; Science & Technology; Chemistry; CTL019
• Research Categories: Chemistry, Biochemistry; Biology, Cell; Health Sciences, Pathology

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.