| Autor: |
Wendell A. Lim, Milos S. Simic, Kira M. Downey, Aileen W. Li, Jessica D. Briones, Anna Celli, Nira A. Krasnow, Wei Yu, Choe Joseph H, Lia Cardarelli, Payal Watchmaker, Kole T. Roybal, Diego A. Carrera, Sachdev S. Sidhu, Ryan Gilbert, Juhyun Cho, Hideho Okada, Ruth Dannenfelser |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.01.07.425632 |
| Popis: |
Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of target antigens that are both tumor-specific and homogeneously expressed. We show that multiantigen prime-and-kill recognition circuits have the flexibility and precision to overcome these challenges in attacking glioblastoma. A synNotch receptor that recognizes a specific priming antigen – the heterogeneous glioblastoma neoantigen EGFRvIII or a brain tissue-specific antigen – is used to locally induce expression of a CAR, enabling thorough but controlled tumor killing by targeting of homogeneous antigens that are not absolutely tumor specific. Moreover, regulated CAR expression maintains a higher fraction of the T cells in the naïve-like state which is associated with higher durability in vivo. In summary, using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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