The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent
Open accessAbstract
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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Cites
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Cited by
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Majzner, R. G., & Mackall, C. L. (2019) · Nature Medicine · doi:10.1038/s41591-019-0564-6 · Cited by 636
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Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells
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GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells
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Emerging Cellular Therapies for Cancer
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Metadata
- 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)
- OpenAlex
- W2761657464
- Cited by
- 285
- References
- 46
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- gold
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- The paper
- 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. (2017). Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent. Cell Reports. https://doi.org/10.1016/j.celrep.2017.09.015
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
