Chabi Sara, To Thi Hong Van, Leavitt Ron, Poglio Sandrine, Jorge Patrik Gonçalves, Jaccard Maud, Petersson Kristoffer, Petit Benoit, Roméo Paul-Henri, Pflumio Françoise, Vozenin Marie-Catherine, Uzan Benjamin
Team Niche and Cancer in Hematopoiesis, Fontenay-aux-Roses, France; Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Service Cellules Souches et Radiations, Fontenay-aux-Roses, France; UMRE008 Stabilité Génétique, Cellules Souches et Radiations, Université de Paris and Université Paris-Saclay, Fontenay-aux-Roses, France.
Laboratoire des cellules Souches Hématopoïétiques et des Leucémies, Service Cellules Souches et Radiations, Fontenay-aux-Roses, France; UMRE008 Stabilité Génétique, Cellules Souches et Radiations, Université de Paris and Université Paris-Saclay, Fontenay-aux-Roses, France; Laboratory of Radiation Oncology, Department of Radiation Oncology, Lausanne University Hospital and University of Lausanne, Switzerland.
Int J Radiat Oncol Biol Phys. 2021 Mar 1;109(3):819-829. doi: 10.1016/j.ijrobp.2020.10.012. Epub 2020 Oct 17.
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 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 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.
超高剂量率闪疗已被证明可在保持抗肿瘤疗效的同时，将各器官的辐射副作用降至最低。这种特性，即闪射效应，在放射肿瘤学界引发了热潮，因为它为安全提高剂量和改善放疗效果带来了机遇。在此，我们研究了超高剂量率闪射与常规剂量率（CONV）全身照射（TBI）对T细胞急性淋巴细胞白血病（T-ALL）人源化模型和正常人类造血的影响。
我们优化了照射几何结构，以确保使用eRT6/Oriatron进行可重复且均匀的操作。将3例T-ALL患者来源的异种移植瘤以及从脐带血中分离的造血干/祖细胞（HSPCs）和CD34细胞一起或分别移植到免疫缺陷小鼠体内。重建后，小鼠接受4 Gy的闪射和CONV-TBI，并研究肿瘤生长和正常造血情况。对先前在这3例T-ALL患者来源的异种移植瘤上获得的临床和基因谱数据进行了回顾性研究。
闪射-TBI在控制2例T-ALL的增殖方面比CONV-TBI更有效，而第3例T-ALL对CONV-TBI反应更强。2例对闪射敏感的T-ALL病例具有相似的基因异常，并且发现了对闪射放疗的假定易感性印记。此外，闪射-TBI能够保留一些HSPC/CD34细胞潜能。有趣的是，当HSPC和T-ALL存在于同一动物体内时，闪射-TBI可在大多数（4例中的3例）二次移植动物中控制肿瘤发展，而在接受CONV-TBI的小鼠中，处理后的细胞因白血病浸润严重而死亡。
与CONV-TBI相比，闪射-TBI减少了对人类血液干细胞的功能损伤，并对具有共同基因和基因组特征的人类T-ALL具有治疗作用。所定义的易感性印记的有效性需要进一步研究；然而，据我们所知，目前的研究结果首次显示了闪射-TBI对人类造血和白血病治疗的益处。
