4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Antigen Independent Signaling of Chimeric Antigen Receptors
說明
165 p
附註
Source: Dissertation Abstracts International, Volume: 77-02(E), Section: B
Adviser: Crystal L. Mackall
Thesis (Ph.D.)--Northwestern University, 2015
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
