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Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent

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Gomes-Silva, Diogo, Mukherjee, Malini, Srinivasan, Madhuwanti, Krenciute, Giedre, Dakhova, Olga, Zheng, Yueting, Cabral, Joaquim M.S., Rooney, Cliona M., Orange, Jordan S., Brenner, Malcolm K., Mamonkin, Maksim·2017·Cell Reports

DOI 10.1016/j.celrep.2017.09.015

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Abstract

Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB) pathway and augmented FAS-dependent cell death. This mechanism was amplified in a non-self-inactivating gammaretroviral vector through positive feedback on the long terminal repeat (LTR) promoter, further enhancing CAR expression and tonic signaling. Attenuating CAR expression by substitution with a self-inactivating lentiviral vector minimized tonic signaling and improved T cell expansion and anti-tumor function. These studies illuminate the interaction between tonic CAR signaling and the chosen expression platform and identify inhibitory properties of the 4-1BB costimulatory domain that have direct implications for rational CAR design.

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Authors: Gomes-Silva, D., Mukherjee, M., Srinivasan, M., Krenciute, G., Dakhova, O., Zheng, Y., Cabral, J. M. S., Rooney, C. M., Orange, J. S., Brenner, M. K., & Mamonkin, M.
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2017-10
Volume: 21
Issue: 1
Pages: 17-26
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2017.09.015
OpenAlex: W2761657464
Cited by: 285
References: 46
FWCI: 10.45
Type: journal article
Language: en
Open access: gold

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Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent

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