Overcoming target epitope masking resistance that can occur on low-antigen-expresser AML blasts after IL-1RAP chimeric antigen receptor T cell therapy using the inducible caspase 9 suicide gene safety switch.
Animals
Caspase 9
/ metabolism
Cell- and Tissue-Based Therapy
/ methods
Disease Models, Animal
Epitopes
/ metabolism
Humans
Immunotherapy
/ methods
Leukemia, Myeloid, Acute
/ genetics
Mice
Receptors, Chimeric Antigen
/ metabolism
Receptors, Interleukin-1
/ metabolism
Xenograft Model Antitumor Assays
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
06
09
2020
accepted:
04
12
2020
revised:
27
11
2020
pubmed:
9
1
2021
medline:
3
3
2022
entrez:
8
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33414517
doi: 10.1038/s41417-020-00284-3
pii: 10.1038/s41417-020-00284-3
pmc: PMC8636256
doi:
Substances chimiques
Epitopes
0
Receptors, Chimeric Antigen
0
Receptors, Interleukin-1
0
Caspase 9
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1365-1375Informations de copyright
© 2021. The Author(s).
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