Journal
ONCOLOGY REPORTS
Volume 46, Issue 2, Pages -Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2021.8121
Keywords
CD19; chimeric antigen receptor; T cells; selective nuclear export inhibitor; selinexor; eltanexor; STAT3; nuclear exportin-1
Categories
Funding
- Olympia Morata Program of the Medical Faculty of Heidelberg
- China Scholarship Council
Ask authors/readers for more resources
CAR T cells targeting CD19 have shown impressive clinical responses in lymphoid malignancies, but resistance and relapse remain challenges. Combining CAR T cells with selective inhibitors of nuclear export (SINEs) targeting XPO1 may reduce the risk of tumor escape, although simultaneous use of SINEs and CAR T cells may impair CAR T cell function. Sequential use of SINEs and CAR T cells could potentially enhance the anti-tumor efficacy of CAR T cells.
Chimeric antigen receptor (CAR) T cells directed against CD19 (CD19.CAR T cells) have yielded impressive clinical responses in the treatment of patients with lymphoid malignancies. However, resistance and/or relapse can limit treatment outcome. Risk of tumor escape can be reduced by combining treatment strategies. Selective inhibitors of nuclear export (SINEs) directed against nuclear exportin-1 (XPO1) have demonstrated anti-tumor efficacy in several hematological malignancies. The aim of the present study was to evaluate the combination of CAR T cells with the SINE compounds eltanexor and selinexor. As expected, eltanexor and selinexor were toxic to CD19-positive malignant cells and the sensitivity of cells towards SINEs correlated with the levels of XPO1-expression in ALL cell lines. When SINEs and CAR T cells were simultaneously combined, SINEs exerted toxicity towards CAR T cells and impaired their function affecting cytotoxicity and cytokine release ability. Flow cytometry and western blot analysis revealed that eltanexor decreased the cytoplasmic concentration of the transcription factor phosphorylated-STAT3 in CAR T cells. Due to CAR T-cell toxicity, sequential use of SINEs and CAR T cells was evaluated: Cytotoxicity of CAR T cells increased significantly when target cells were pre-treated with the SINE compound eltanexor. In addition, exhaustion of CAR T cells decreased when target cells were pre-treated with eltanexor. In summary, whereas the concomitant use of SINEs and CAR T cells does not seem advisable, sequential use of SINEs and CAR T cells might improve the anti-tumor efficacy of CAR T cells.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available