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

Frontiers in Medicine

Paul A. Castillo¹  Haruko Tashiro¹  Michael Schmueck-Henneresse¹  Andrew Lewis¹  Mara Cardenas¹  Miyuki Tanaka¹  Mai T. A. Huynh¹  Thomas Shum¹  Tim Sauer¹  Natalia Lapteva¹  Malini Mukherjee¹  Cliona M. Rooney²  Stephen Gottschalk³  Robin Parihar⁴  Bilal Omer⁴ 

[1] Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children's Hospital, Houston, TX, United States;Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States;Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States;Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States;

关键词: adoptive cell therapy;    chimeric antigen receptor;    virus specific t cells;    t cell receptor;    signaling domains;   

DOI  :  10.3389/fmed.2018.00343

来源: DOAJ

【 摘 要 】

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 (ζ) 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.CD28ζ-VZVSTs was 3.3-fold greater (p < 0.001) than non-transduced VZVSTs, whereas GD2-CARζ- and GD2-CAR.41BBζ inhibited VZVST expansion (p < 0.01). Compared to control VZVSTs, GD2-CAR.ζ VZVSTs showed a greater frequency of apoptotic (p < 0.01) T cells, whereas prolonged downregulation of the native αβ TCR was observed in GD2-CAR.41BBζ VZVSTs (p < 0.001). We confirmed that CD28ζ 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 CD28ζ endodomains also showed the greatest expansion (6 fold > GD2-CAR.41BBζ VZVSTs (p < 0.001), however anti-tumor efficacy was superior in GD2-CAR.41BBζ-VZVSTs. These findings demonstrate that CAR signaling domains can enhance or diminish the function of the native TCR and indicate that only CD28ζ may preserve the function of the native TCR in tonically signaling CAR-VSTs.

【 授权许可】

Unknown