PuSH - Publication Server of Helmholtz Zentrum München: T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals.

Information

Clues to quality of journals

Open Access Policy of Helmholtz Association 2016

CC Licencences

Publication Metrics

Navigation

Home

Deutsch

EVA: Electronic Publishing

New EVA Application

Research

Advanced Search

Browse by ...

... HMGU-Authors/Consortia

... Organizational Structure

... Journal

... Publication Type

... Research Data

... Arbeitsgruppen

... Publication Year

Publication overview

Statistics

Statistics (last 5 years)

OA Publications

Publish

Submit Publication

Import publication from...

...EVA

Report missing publication

Highlights

Support & Contact

Contact persons

Help

Data protection

Helmholtz Open Science

JANE Journal Estimator

SHERPA/RoMEO

DOAJ

Export:

Text

Endnote (RIS) BIB

BibTeX

Philipp, N.* ; Kazerani, M.* ; Nicholls, A.* ; Vick, B. ; Wulf, J.* ; Straub, T.* ; Scheurer, M.* ; Muth, A.* ; Hänel, G.* ; Nixdorf, D.* ; Sponheimer, M.* ; Ohlmeyer, M.* ; Lacher, S.M.* ; Brauchle, B.* ; Marcinek, A.* ; Rohrbacher, L.* ; Leutbecher, A.* ; Rejeski, K.* ; Weigert, O.* ; von Bergwelt-Baildon, M.* ; Theurich, S.* ; Kischel, R.* ; Jeremias, I. ; Bücklein, V.* ; Subklewe, M.*

T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals.

Blood 140, 1104-1118 (2022)

Publ. Version/Full Text

Research data

DOI

	Open Access Hybrid

Abstract
Metrics
Extra information

T-cell–recruiting bispecific molecule therapy has yielded promising results in patients with hematologic malignancies; however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell–based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific molecule blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life–extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; P = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as a powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI-specific lysis on day 14: 34.9% vs 93.4%; n = 6; P < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.

Impact Factor

Scopus SNIP

Scopus
Cited By

Altmetric

25.476

3.105