For days after treatment, patients in early radioimmunotherapy trials at Fred Hutch were confined to lead-lined rooms, not because they were sick, but because they had become temporarily radioactive.
The idea of unleashing radiation inside the body to hunt down cancer cells sounds unsettling, yet it is highly effective for treating certain blood cancers. By attaching radioactive agents to antibodies that recognize specific cell surface markers, radioimmunotherapy delivers radiation directly to its target. Unlike total body irradiation, a long-standing conditioning regimen used before stem cell transplantation, radioimmunotherapy offers a more precise approach.
But this kind of precision has its limits. At the cellular level, radioimmunotherapy behaves like an explosion, damaging not only the intended target but also any neighboring cells caught in its tiny blast radius.
The first generation of radioimmunotherapy agents used beta emitters, radioactive elements that dispense a low radiation payload over a long distance. But the field is shifting toward using alpha emitters like Astatine-211 (211At), which delivers a more powerful dose of radiation over a range of just a few cell diameters. In theory, this short-range, high-energy approach should concentrate damage within targeted cells while limiting harm to surrounding tissue.
Nowhere is this more important than in the bone marrow. Contained within it are hematopoietic stem cells, the progenitors of every blood and immune cell in the body. Surrounding these cells is an intricate support network of blood vessels and stromal cells that help regulate their growth and recovery after injury. In the complex environment of the bone marrow, the collateral effects of targeted radiation can shape how the blood and immune system rebuilds itself after treatment. Slow recovery can leave patients at risk for hemorrhage or infection.
Researchers at Fred Hutch have continued to develop and study radioimmunotherapy, with clinical trials currently underway looking at 211At targeted to CD45, a marker highly expressed on the surface of hematopoietic cells. But the cellular and molecular effects of this targeted radiation are not yet fully understood. A recent study from the Termini and Orozco labs in the Translational Science and Therapeutics division set out to understand the effects of this targeted approach on the bone marrow environment.
The study compared three different treatment approaches in healthy, immunocompetent mice: CD45-targeted 211At radioimmunotherapy, non-targeted 211At radioimmunotherapy, and non-targeted external total body irradiation with the beta and gamma emitter Cesium-137. Blood and bone marrow samples were collected and analyzed at different timepoints after the treatment.
Their findings suggest that even when 211At radiation is carefully directed to hematopoietic cells, its effects can ripple outward, altering neighboring cells and reshaping blood vessels in ways that may influence how the entire system recovers. Bone marrow hematopoietic stem and progenitor cells were depleted across all treatment conditions, but the CD45-targeted approach drove those levels down more profoundly and kept them low for longer. This effect matters for transplant medicine, where more thorough clearing of the existing hematopoietic system can create better conditions for donor cells to succeed. The stem cells that remained after CD45-targeted treatment also showed changes in their ability to regulate their own cell cycle and differentiate into mature blood cells, which could further influence the pace of recovery.
For lead author Matt Hagen, whose research has long focused on vascular biology, one of the more striking findings involved the bone marrow’s blood vessels. Across all treatment conditions, the vasculature underwent dramatic remodeling in the days following treatment, expanding significantly before gradually returning to normal. In mice that received CD45-targeted therapy, however, that expansion persisted longer.
Endothelial cells, which form the inner walls of blood vessels in the bone marrow, do not express CD45 on their surface, but they sit in close proximity to the hematopoietic cells being targeted. Despite seeing an expansion in the vasculature, the number of endothelial cells did not expand, suggesting sustained damage to the endothelial cells from the targeted treatment.
RNA sequencing of bone marrow endothelial cells showed that CD45-targeted radioimmunotherapy produced a pattern of gene activity distinct from both non-targeted radiation and untreated controls. Genes involved in cell growth, programmed cell death, and new blood vessel formation changed in the CD45-targeted group. Distinct changes were also reflected at the protein level, suggesting that the transcriptional shifts translated into functional consequences for the cells.
Whether these shifts ultimately help or hinder the recovery is still unknown. But they underscore the idea that even highly targeted therapies can have broader consequences. This was the first study to assess 211At-targeted radioimmunotherapy in healthy animals, helping researchers understand how a healthy organism responds to the treatment when all biological processes are operating normally, before extrapolating to the far more complex context of cancer.
This study lays the groundwork for understanding how the bone marrow environment breaks down and rebuilds itself at the cellular and molecular level. It also raises important questions about whether and how these structural and cellular disruptions affect patient outcomes. Insights from this work could help reshape how these treatments are designed, delivered, and monitored to improve recovery while preserving the effectiveness of radioimmunotherapy.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Dr. Johnnie Orozco and Dr. Christina Termini contributed to this research.
The spotlighted research was funded by the National Institutes of Health.
Hagen MW, Setiawan NJ, Dexter S, Woodruff KA, Gaerlan FK, Billings TM, Orozco JJ, and Termini CM. 2026. The bone marrow niche and hematopoietic system are distinctly remodeled by CD45-targeted astatine-211 radioimmunotherapy. Blood Advances. DOI: 10.1182/bloodadvances.2025017065.
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.
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