The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape
Open accessAbstract
In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.
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Cites
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Metadata
- Authors
- Hegde, M., Mukherjee, M., Grada, Z., Pignata, A., Landi, D., Navai, S. A., Wakefield, A., Fousek, K., Bielamowicz, K., Chow, K. K. H., Brawley, V. S., Byrd, T. T., Krebs, S., Gottschalk, S., Wels, W. S., Baker, M. L., Dotti, G., Mamonkin, M., Brenner, M. K., Orange, J. S., & Ahmed, N.
- Venue
- Journal of Clinical Investigation
- Published
- 2016-07-18
- Volume
- 126
- Issue
- 8
- Pages
- 3036-3052
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- OpenAlex
- W2481298264
- Cited by
- 677
- References
- 42
- FWCI
- 25.19
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Hegde, M., Mukherjee, M., Grada, Z., Pignata, A., Landi, D., Navai, S. A., Wakefield, A., Fousek, K., Bielamowicz, K., Chow, K. K. H., Brawley, V. S., Byrd, T. T., Krebs, S., Gottschalk, S., Wels, W. S., Baker, M. L., Dotti, G., Mamonkin, M., Brenner, M. K., . . . Ahmed, N. (2016). Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. Journal of Clinical Investigation. https://doi.org/10.1172/jci83416
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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