Sara Chabi1, Thi Hong Van To2, Ron Leavitt3, Sandrine Poglio1, Patrik Gonçalves Jorge4, Maud Jaccard5, Kristoffer Petersson4, Benoit Petit3, Paul-Henri Roméo6, Françoise Pflumio1, Marie-Catherine Vozenin7, Benjamin Uzan1. 1. 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. 2. 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. 3. Laboratory of Radiation Oncology, Department of Radiation Oncology, Lausanne University Hospital and University of Lausanne, Switzerland. 4. Laboratory of Radiation Oncology, Department of Radiation Oncology, Lausanne University Hospital and University of Lausanne, Switzerland; Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland. 5. Institute of Radiation Physics/CHUV, Lausanne University Hospital, Switzerland. 6. Team Niche and Cancer in Hematopoiesis, Fontenay-aux-Roses, France; UMRE008 Stabilité Génétique, Cellules Souches et Radiations, Université de Paris and Université Paris-Saclay, Fontenay-aux-Roses, France; Laboratoire de la Régulation de la Transcription dans les cellules Souches, Service Cellules Souches et Radiations, Fontenay-aux-Roses, France. 7. Laboratory of Radiation Oncology, Department of Radiation Oncology, Lausanne University Hospital and University of Lausanne, Switzerland. Electronic address: mcatvozenin@gmail.com.
Abstract
PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.
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