TY - JOUR
T1 - First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies
AU - Zuro, Darren
AU - Madabushi, Srideshikan Sargur
AU - Brooks, Jamison
AU - Chen, Bihong T.
AU - Goud, Janagama
AU - Salhotra, Amandeep
AU - Song, Joo Y.
AU - Parra, Liliana Echavarria
AU - Pierini, Antonio
AU - Sanchez, James F.
AU - Stein, Anthony
AU - Malki, Monzr Al
AU - Kortylewski, Marcin
AU - Wong, Jeffrey Y.C.
AU - Alaei, Parham
AU - Froelich, Jerry
AU - Storme, Guy
AU - Hui, Susanta K.
N1 - Funding Information:
Research reported in this publication is supported by the National Institutes of Health (2R01CA154491-01) (SH), and partly supported by ONCOTEST (Ghent, Belgium) (SH). The Small Animal Imaging Core at City of Hope is supported by P30CA033572.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/11/1
Y1 - 2021/11/1
N2 - Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models. Methods and Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo–based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry. Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI. Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
AB - Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models. Methods and Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo–based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry. Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI. Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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U2 - 10.1016/j.ijrobp.2021.06.001
DO - 10.1016/j.ijrobp.2021.06.001
M3 - Article
C2 - 34119592
AN - SCOPUS:85109752210
SN - 0360-3016
VL - 111
SP - 671
EP - 683
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 3
ER -