MARC 主機 00000nam a2200325 4500 001 AAI3724304 005 20161114130330.5 008 161114s2015 ||||||||s|||||||| ||eng d 020 9781339077734 035 (MiAaPQ)AAI3724304 040 MiAaPQ|cMiAaPQ 100 1 Long, Adrienne Hart 245 10 4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Antigen Independent Signaling of Chimeric Antigen Receptors 300 165 p 500 Source: Dissertation Abstracts International, Volume: 77- 02(E), Section: B 500 Adviser: Crystal L. Mackall 502 Thesis (Ph.D.)--Northwestern University, 2015 520 Genetically modifying T cells with chimeric antigen receptors (CARs) provides a promising new approach for the adoptive immunotherapy of cancer. CARs are synthetic immune receptors that link antigen binding domains with T cell signaling domains to endow T cells with non-MHC restricted specificity for cell surface antigens. CARs targeting CD19 have mediated dramatic anti-tumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We discovered that tonic CAR CD3- zeta phosphorylation, triggered by antigen-independent clustering of CAR scFvs, can induce early exhaustion of CAR T cells that limits anti-tumor efficacy. Such activation is present to varying degrees in all CARs studied, with the exception of the highly effective CD19 CAR. We further identify that CD28 costimulation augments, while 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Transcriptional profiling of CAR T cells suggested that 4-1BB ameliorates exhaustion in part by decreasing expression of known exhaustion related genes, but may also modulate metabolism, apoptosis, and/or response to hypoxia pathways. Our results provide biological explanations for the dramatic anti-tumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials 590 School code: 0163 650 4 Immunology 650 4 Oncology 690 0982 690 0992 710 2 Northwestern University.|bLife Sciences 773 0 |tDissertation Abstracts International|g77-02B(E) 856 40 |uhttp://pqdd.sinica.edu.tw/twdaoapp/servlet/ advanced?query=3724304 912 PQDT
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