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
