Chimeric Antigen Receptor Signaling Domains Differentially Regulate Proliferation and Native T Cell Receptor Function in Virus-Specific T Cells.

ABSTRACT: The efficacy of T cells expressing chimeric antigen receptors (CARs) for solid tumors has been limited by insufficient CAR T cell expansion and persistence. The use of virus-specific T cells (VSTs) as carriers for CARs may overcome this limitation since CAR-VSTs can be boosted by viral vaccines or oncolytic viruses. However, there is limited understanding of the optimal combination of endodomains and their influence on the native T cell receptor (TCR) in VSTs. We therefore compared the function of GD2.CARs expressing the TCR zeta chain (?) alone or combined with endodomains from CD28 and 4-1BB in varicella zoster virus-specific (VZV) T cells. VZVSTs expressing GD2-CARs recognized VZV-derived peptides and killed GD2-expressing tumor cells. However, after repeated stimulation through their native TCR, the expansion of GD2-CAR.CD28?-VZVSTs was 3.3-fold greater (p < 0.001) than non-transduced VZVSTs, whereas GD2-CAR?- and GD2-CAR.41BB? inhibited VZVST expansion (p < 0.01). Compared to control VZVSTs, GD2-CAR.? VZVSTs showed a greater frequency of apoptotic (p < 0.01) T cells, whereas prolonged downregulation of the native ?? TCR was observed in GD2-CAR.41BB? VZVSTs (p < 0.001). We confirmed that CD28? can best maintain TCR function by expressing GD2.CARs in Epstein-Barr virus-specific T cells and CD19-CARs in VZVSTs. In response to CAR stimulation VSTs with CD28? endodomains also showed the greatest expansion (6 fold > GD2-CAR.41BB? VZVSTs (p < 0.001), however anti-tumor efficacy was superior in GD2-CAR.41BB?-VZVSTs. These findings demonstrate that CAR signaling domains can enhance or diminish the function of the native TCR and indicate that only CD28? may preserve the function of the native TCR in tonically signaling CAR-VSTs.

SUBMITTER: Omer B 

PROVIDER: S-EPMC6297364 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature