Ultra-high-dose-rate FLASH and Conventional-Dose-Rate Irradiation Differentially Affect Human Acute Lymphoblastic Leukemia and Normal Hematopoiesis.

Details

Serval ID
serval:BIB_0D2E39BA99D3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Ultra-high-dose-rate FLASH and Conventional-Dose-Rate Irradiation Differentially Affect Human Acute Lymphoblastic Leukemia and Normal Hematopoiesis.
Journal
International journal of radiation oncology, biology, physics
Author(s)
Chabi S., To THV, Leavitt R., Poglio S., Jorge P.G., Jaccard M., Petersson K., Petit B., Roméo P.H., Pflumio F., Vozenin M.C., Uzan B.
ISSN
1879-355X (Electronic)
ISSN-L
0360-3016
Publication state
Published
Issued date
01/03/2021
Peer-reviewed
Oui
Volume
109
Number
3
Pages
819-829
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Ultra-high-dose-rate FLASH radiation therapy has been shown to minimize side effects of irradiation in various organs while keeping antitumor efficacy. This property, called the FLASH effect, has caused enthusiasm in the radiation oncology community because it opens opportunities for safe dose escalation and improved radiation therapy outcome. Here, we investigated the impact of ultra-high-dose-rate FLASH versus conventional-dose-rate (CONV) total body irradiation (TBI) on humanized models of T-cell acute lymphoblastic leukemia (T-ALL) and normal human hematopoiesis.
We optimized the geometry of irradiation to ensure reproducible and homogeneous procedures using eRT6/Oriatron. Three T-ALL patient-derived xenografts and hematopoietic stem/progenitor cells (HSPCs) and CD34 <sup>+</sup> cells isolated from umbilical cord blood were transplanted into immunocompromised mice, together or separately. After reconstitution, mice received 4 Gy FLASH and CONV-TBI, and tumor growth and normal hematopoiesis were studied. A retrospective study of clinical and gene-profiling data previously obtained on the 3 T-ALL patient-derived xenografts was performed.
FLASH-TBI was more efficient than CONV-TBI in controlling the propagation of 2 cases of T-ALL, whereas the third case of T-ALL was more responsive to CONV-TBI. The 2 FLASH-sensitive cases of T-ALL had similar genetic abnormalities, and a putative susceptibility imprint to FLASH-RT was found. In addition, FLASH-TBI was able to preserve some HSPC/CD34 <sup>+</sup> cell potential. Interestingly, when HSPC and T-ALL were present in the same animals, FLASH-TBI could control tumor development in most (3 of 4) of the secondary grafted animals, whereas among the mice receiving CONV-TBI, treated cells died with high leukemia infiltration.
Compared with CONV-TBI, FLASH-TBI reduced functional damage to human blood stem cells and had a therapeutic effect on human T-ALL with a common genetic and genomic profile. The validity of the defined susceptibility imprint needs to be investigated further; however, to our knowledge, the present findings are the first to show benefits of FLASH-TBI on human hematopoiesis and leukemia treatment.
Pubmed
Web of science
Open Access
Yes
Create date
26/10/2020 15:03
Last modification date
08/05/2021 6:32
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