Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/ijms19124118
Keywords
CTL019; tisagenlecleucel; oligoclonal T cell expansion; DLBCL; T cell immunoglobulin mucin domain 3 (Tim-3); programmed cell death protein 1 (PD-1)
Funding
- Howard Hughes Medical Research Fellowship
- Abraham J. and Phyllis Katz Foundation [00034291]
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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 -peptide variable region of the T cell receptor (TCR) 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 approximate to 50%; PD-1 approximate to 17%) and CAR T cell subsets (Tim-3 approximate to 78%; PD-1 approximate to 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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