The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Functional Tuning of CARs Reveals Signaling Threshold above Which CD8+ CTL Antitumor Potency Is Attenuated due to Cell Fas–FasL-Dependent AICD
Abstract
Chimeric antigen receptor (CAR) development is biased toward selecting constructs that elicit the highest magnitude of T-cell functional outputs. Here, we show that components of CAR extracellular spacer and cytoplasmic signaling domain modulate, in a cooperative manner, the magnitude of CD8+CTL activation for tumor-cell cytolysis and cytokine secretion. Unexpectedly, CAR constructs that generate the highest in vitro activity, either by extracellular spacer length tuning or by the addition of cytoplasmic signaling modules, exhibit attenuated antitumor potency in vivo, whereas CARs tuned for moderate signaling outputs mediate tumor eradication. Recursive CAR triggering renders CTLs expressing hyperactive CARs highly susceptible to activation-induced cell death (AICD) as a result of augmented FasL expression. CAR tuning using combinations of extracellular spacers and cytoplasmic signaling modules, which limit AICD of CD8+CTLs, may be a critical parameter for achieving clinical activity against solid tumors. Cancer Immunol Res; 3(4); 368–79. ©2015 AACR.
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Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia
Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., Teachey, D. T., Chew, A., Hauck, B., Wright, J. F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215134 · Cited by 3,509
Brentjens, R. J., Davila, M. L., Riviere, I., Park, J., Wang, X., Cowell, L. G., Bartido, S., Stefanski, J., Taylor, C., Olszewska, M., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005930 · Cited by 2,063
NFATc1 Regulates PD-1 Expression upon T Cell Activation
Oestreich, K. J., Yoon, H., Ahmed, R., & Boss, J. M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.7.4832 · Cited by 416
Graef, P., Buchholz, V. R., Stemberger, C., Flossdorf, M., Henkel, L., Schiemann, M., Drexler, I., Höfer, T., Riddell, S. R., & Busch, D. H. (2014) · Immunity · doi:10.1016/j.immuni.2014.05.018 · Cited by 311
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CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy
Pan, K., Farrukh, H., Chittepu, V. C. S. R., Xu, H., Pan, C.-X., & Zhu, Z. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02327-z · Cited by 657
Zah, E., Lin, M.-Y., Silva-Benedict, A., Jensen, M. C., & Chen, Y. Y. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0231 · Cited by 607
Self-citationKilling Mechanisms of Chimeric Antigen Receptor (CAR) T Cells
Benmebarek, M.-R., Karches, C. H., Cadilha, B. L., Lesch, S., Endres, S., & Kobold, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061283 · Cited by 531
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., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.015 · Cited by 285
Vitanza, N. A., Wilson, A. L., Huang, W., Seidel, K., Brown, C., Gustafson, J. A., Yokoyama, J. K., Johnson, A. J., Baxter, B. A., Koning, R. W., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0750 · Cited by 279
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Metadata
- Authors
- Künkele, A., Johnson, A. J., Rolczynski, L. S., Chang, C. A., Hoglund, V., Kelly-Spratt, K. S., & Jensen, M. C.
- Venue
- Cancer Immunology Research
- Published
- 2015-04-01
- Volume
- 3
- Issue
- 4
- Pages
- 368-379
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- OpenAlex
- W2110002127
- Cited by
- 182
- References
- 4
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- closed
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- Künkele, A., Johnson, A. J., Rolczynski, L. S., Chang, C. A., Hoglund, V., Kelly-Spratt, K. S., & Jensen, M. C. (2015). Functional Tuning of CARs Reveals Signaling Threshold above Which CD8+ CTL Antitumor Potency Is Attenuated due to Cell Fas–FasL-Dependent AICD. Cancer Immunology Research. https://doi.org/10.1158/2326-6066.cir-14-0200
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