Molecular monitoring of T-cell kinetics and migration in severe neurotoxicity after real-world CD19-specific chimeric antigen receptor-T cell therapy

TY - JOUR

T1 - Molecular monitoring of T-cell kinetics and migration in severe neurotoxicity after real-world CD19-specific chimeric antigen receptor-T cell therapy

AU - Berger, Susanna Carolina

AU - Fehse, Boris

AU - Akyüz, Nuray

AU - Geffken, Maria

AU - Wolschke, Christine

AU - Janson, Dietlinde

AU - Gagelmann, Nico

AU - Luther, Marlene

AU - Wichmann, Dominic

AU - Frenzel, Christian

AU - Thayssen, Guenther

AU - Alegiani, Anna

AU - Badbaran, Anita

AU - Zeschke, Silke

AU - Dierlamm, Judith

AU - Kröger, Nicolaus

AU - Ayuk, Francis A

PY - 2023/2/1

Y1 - 2023/2/1

N2 - CD19-specific chimeric antigen receptor (CD19-CAR) T-cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANSdirected therapies (especially corticosteroids) has been observed. Recent data suggest that inflammatory cytokines and/or targeting of cerebral CD19-expressing pericytes can disrupt the blood-brain barrier and facilitate influx of immune cells, including CAR T cells. However, specific tools for CD19-CAR T-cell analysis within often minute samples of cerebrospinal fluid (CSF) are not broadly available. Here, we applied our recently developed digital polymerase chain reaction assays to monitor CD19-CAR T-cell kinetics in CSF and blood in real-world patients with neurotoxicity. Consistently, we observed a CAR T-cell enrichment within CSF in ICANS patients with further progressive accumulation despite intense corticosteroid- containing immuno-chemotherapies in a subset of patients with prolonged and therapy-resistant grade 3-4 neurotoxicity. We used next-generation T-cell receptor-b sequencing to assess the repertoire of treatment-refractory cells. Longitudinal analysis revealed a profound skewing of the T-cell receptor repertoire, which at least partly reflected selective expansion of infused T-cell clones. Interestingly, a major fraction of eventually dominating hyperexpanded T-cell clones were of non-CAR T-cell derivation. These findings hint to a role of therapy-refractory T-cell clones in severe ICANS development and prompt future systematic research to determine if CAR T cells may serve as 'door openers' and to further characterize both CAR-positive and non-CAR T cells to interrogate the transcriptional signature of these possibly pathologic T cells.

AB - CD19-specific chimeric antigen receptor (CD19-CAR) T-cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANSdirected therapies (especially corticosteroids) has been observed. Recent data suggest that inflammatory cytokines and/or targeting of cerebral CD19-expressing pericytes can disrupt the blood-brain barrier and facilitate influx of immune cells, including CAR T cells. However, specific tools for CD19-CAR T-cell analysis within often minute samples of cerebrospinal fluid (CSF) are not broadly available. Here, we applied our recently developed digital polymerase chain reaction assays to monitor CD19-CAR T-cell kinetics in CSF and blood in real-world patients with neurotoxicity. Consistently, we observed a CAR T-cell enrichment within CSF in ICANS patients with further progressive accumulation despite intense corticosteroid- containing immuno-chemotherapies in a subset of patients with prolonged and therapy-resistant grade 3-4 neurotoxicity. We used next-generation T-cell receptor-b sequencing to assess the repertoire of treatment-refractory cells. Longitudinal analysis revealed a profound skewing of the T-cell receptor repertoire, which at least partly reflected selective expansion of infused T-cell clones. Interestingly, a major fraction of eventually dominating hyperexpanded T-cell clones were of non-CAR T-cell derivation. These findings hint to a role of therapy-refractory T-cell clones in severe ICANS development and prompt future systematic research to determine if CAR T cells may serve as 'door openers' and to further characterize both CAR-positive and non-CAR T cells to interrogate the transcriptional signature of these possibly pathologic T cells.

U2 - 10.3324/haematol.2022.281110

DO - 10.3324/haematol.2022.281110

M3 - SCORING: Journal article

C2 - 35950534

VL - 108

SP - 444

EP - 456

JO - HAEMATOLOGICA

JF - HAEMATOLOGICA

SN - 0390-6078

IS - 2

ER -