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CD38‐Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells.
- Source :
-
Advanced Science . Sep2023, Vol. 10 Issue 27, p1-16. 16p. - Publication Year :
- 2023
-
Abstract
- The robust and stable expression of CD38 in T‐cell acute lymphoblastic leukemia (T‐ALL) blasts makes CD38 chimeric antigen receptor (CAR)‐T/natural killer (NK) a potential therapy for T‐ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR‐T/NK cells. Here a "2‐in‐1" gene editing strategy is developed to generate fratricide‐resistant locus‐specific CAR‐T/NK cells. CD38‐specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI) or exogenous EF1α promoter (CD38KO/KIEF1α). CD38 knockout reduces fratricide and allows the expansion of CAR‐T cells. Meanwhile, CD38KO/KIEF1α results in higher CAR expression than CD38KO/KI in both CAR‐T and CAR‐NK cells. In a mouse T‐ALL model, CD38KO/KIEF1α CAR‐T cells eradicate tumors better than CD38KO/KI CAR‐T cells. Surprisingly, CD38KO/KI CAR‐NK cells show superior tumor control than CD38KO/KIEF1α CAR‐NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR‐T and CAR‐NK cells differently. Therefore, these results support the efficacy of CD38 CAR‐T/NK against T‐ALL and demonstrate that the "2‐in‐1" strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 21983844
- Volume :
- 10
- Issue :
- 27
- Database :
- Academic Search Index
- Journal :
- Advanced Science
- Publication Type :
- Academic Journal
- Accession number :
- 172346664
- Full Text :
- https://doi.org/10.1002/advs.202207394