The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma
Open accessAbstract
Background: Glioblastoma (GBM) is the most common primary malignant brain cancer, and is currently incurable. Chimeric antigen receptor (CAR) T cells have shown promise in GBM treatment. While we have shown that combinatorial targeting of 2 glioma antigens offsets antigen escape and enhances T-cell effector functions, the interpatient variability in surface antigen expression between patients hinders the clinical impact of targeting 2 antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application. Methods: We analyzed the surface expression of 3 targetable glioma antigens (human epidermal growth factor receptor 2 [HER2], interleukin-13 receptor subunit alpha-2 [IL13Rα2], and ephrin-A2 [EphA2]) in 15 primary GBM samples. Accordingly, we created a trivalent T-cell product armed with 3 CAR molecules specific for these validated targets encoded by a single universal (U) tricistronic transgene (UCAR T cells). Results: Our data showed that co-targeting HER2, IL13Rα2, and EphA2 could overcome interpatient variability by a tendency to capture nearly 100% of tumor cells in most tumors tested in this cohort. UCAR T cells made from GBM patients' blood uniformly expressed all 3 CAR molecules with distinct antigen specificity. UCAR T cells mediated robust immune synapses with tumor targets forming more polarized microtubule organizing centers and exhibited improved cytotoxicity and cytokine release over best monospecific and bispecific CAR T cells per patient tumor profile. Lastly, low doses of UCAR T cells controlled established autologous GBM patient derived xenografts (PDXs) and improved survival of treated animals. Conclusion: UCAR T cells can overcome antigenic heterogeneity in GBM and lead to improved treatment outcomes.
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Cites
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Self-citationTandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape
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Metadata
- Authors
- Bielamowicz, K., Fousek, K., Byrd, T. T., Samaha, H., Mukherjee, M., Aware, N., Wu, M.-F., Orange, J. S., Sumazin, P., Man, T.-K., Joseph, S. K., Hegde, M., & Ahmed, N.
- Venue
- Neuro-Oncology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-09-16
- Volume
- 20
- Issue
- 4
- Pages
- 506-518
- ISSN
- 1522-8517 (ISSN-L)
- 1523-5866
- OpenAlex
- W2755677601
- Cited by
- 425
- References
- 33
- FWCI
- 12.49
- Type
- journal article
- Language
- en
- Open access
- green
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- Bielamowicz, K., Fousek, K., Byrd, T. T., Samaha, H., Mukherjee, M., Aware, N., Wu, M.-F., Orange, J. S., Sumazin, P., Man, T.-K., Joseph, S. K., Hegde, M., & Ahmed, N. (2018). Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology. https://doi.org/10.1093/neuonc/nox182
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