Asset Details
Do you wish to reserve the book?
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors
Do you wish to request the book?
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors
2015
Overview
Crystal Mackall and colleagues report that antigen-independent signaling of chimeric antigen receptors (CARs) causes T cell exhaustion and reduced therapeutic efficacy of CAR T cells that can be overcome by incorporating the 4-1BB costimulatory domain into the CAR.
Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor 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 show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy. Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the antitumor 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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 13/21
/ 13/31
/ 13/44
/ 14/63
/ 42/109
/ 59/5
/ 64/60
/ 82/80
/ Cancer
/ Hematologic Neoplasms - immunology
/ Hematologic Neoplasms - pathology
/ Hematologic Neoplasms - therapy
/ Humans
/ Lymphocyte Activation - immunology
/ Receptors, Antigen - immunology
/ Receptors, Antigen - metabolism
/ T cells
/ Tumor Necrosis Factor Receptor Superfamily, Member 9 - biosynthesis
/ Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology
/ Tumors
