期刊
CANCER GENE THERAPY
卷 28, 期 12, 页码 1365-1375出版社
SPRINGERNATURE
DOI: 10.1038/s41417-020-00284-3
关键词
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类别
资金
- Programme de Recherche Translationnelle en Cancerologie INCa
- PRTK [PRT-K275]
- Association Nausicaa combat sa Leucemie (non-profit association loi 1901 FR)
- Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGMTC)/Association Capucine Grant [2013-AO2]
- French Blood center
- MiMedi project - BPI France [DOS0060162/00]
- European Union through the European Regional Development Fund of the Region Bourgogne-Franche-Comte [FC0013440]
Although chimeric antigen receptor (CAR) T cell immunotherapies have been successful in treating B malignancies, tumor cells can develop resistance through antigen masking or inactivation of CAR T cells. Researchers have validated this epitope-masking resistance model in acute myeloid leukemia and found that decreased epitope density of IL-1RAP leads to resistance to CAR T cells.
Although chimeric antigen receptor CAR) T cell immunotherapies are an undeniable and unequivocal success, knowledge obtained from the monitoring of the first clinical trials targeting the CD19 antigen in B malignancies, either refractory/relapsed acute lymphoid leukemia (ALL) or lymphomas, contributed to the identification of tumor cell escape in about 30-50% of B-ALL. Resistance occurred due to loss of surface expression of the antigen (rCD19-) or to the early disappearance or inactivation of CAR T cells (rCD19+). In a recently reported clinical case, rCD19- relapse resulted from masking of the antigen by the CAR at the surface of B-ALL leukemia cells following the unexpected viral transduction of a leukemic cell present in the cytapheresis sample. The objective of this work was to reproduce this epitope-masking resistance model, in the context of acute myeloid leukemia (AML), based on our immunotherapeutic CAR T cell model targeting the accessory protein of the interleukin-1 receptor (IL-1RAP) expressed by leukemic stem cells. As AML primary blasts express different levels of IL-1RAP, we modeled transduction of different AML tumor cell lines screened for density of antigenic sites with our lentiviral vectors carrying a third-generation IL-1RAP CAR, an iCASP9 suicide gene, and a truncated CD19 surface gene. We demonstrated that primary AML blasts can be easily transduced (74.55 +/- 21.29%, n = 4) and that CAR T cytotoxicity to IL-1RAP is inversely correlated with epitope masking in relation to the number of antigenic sites expressed on the surface of IL-1RAP+ lines. Importantly, we showed that, in vitro, a 24-h exposure of IL-1RAP+/CAR+ leukemia lines to Rimiducid eliminated >85% of the cells. We confirmed that the expression of IL-1RAP CAR by an IL-1RAP+ leukemic cell, by decreasing the membrane availability of the targeted antigen, can induce resistance while a high epitope density maintains sensitivity to CAR T cells. Moreover, the presence of the iCASP9/Rimiducid suicide system safety switch makes this immunotherapy approach safe for application in a future phase 1 clinical trial.
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