First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies

Darren M Zuro, Srideshikan Sargur Madabushi, Jamison Brooks, Bihong T. Chen, Janagama Goud, Amandeep Salhotra, Joo Y. Song, Liliana Echavarria Parra, Antonio Pierini, James F. Sanchez, Anthony Stein, Monzr Al Malki, Marcin Kortylewski, Jeffrey Y.C. Wong, Parham Alaei, Jerry Froelich, Guy Storme, Susanta K. Hui

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)671-683
Number of pages13
JournalInternational Journal of Radiation Oncology Biology Physics
Volume111
Issue number3
Early online dateJun 11 2021
DOIs
StateE-pub ahead of print - Jun 11 2021

Bibliographical note

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)

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