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While the use of radiation bridging therapy (BT) in chimeric antigen receptor (CAR) T-cell therapy for blood cancer is expanding, plenty of unanswered questions remain on topics such as ideal timing and doses, a radiologist cautioned hematologist colleagues.

The lack of guidelines has immediate clinical implications, said John P. Plastaras, MD, PhD, professor of radiation oncology at the Hospital of the University of Pennsylvania, Philadelphia, in a presentation at 18th International Conference on Malignant Lymphoma (ICML) 2025 in Lugano, Switzerland.

“This actually just came up the other day when one of our medical colleagues said, ‘I’m really worried about this patient. They’re ready for CAR T cell, but I think you need to radiate this area. Can you do it a week after [therapy]?’ The answer is, ‘We don’t know.’”

On the other hand, clinicians now have clarity about safety and interaction with CAR T-cell therapy, he noted, and data is coming in rapidly.

Here are some questions and answers about radiation BT:

What is BT in CAR T-cell therapy?

BT refers to treatment that provides a “bridge” for patients between the components of CAR T-cell therapy.

As a 2024 report about BT in hematologic cancer explained, the treatment “is delivered after leukapheresis for CAR T-cells” — the process in which white cells are removed from a patient’s blood, which is then returned to the body — “has been completed and before lymphodepleting chemotherapy and CAR T-cell infusion.”

The report said “patients who receive BT are predominantly those with a higher disease burden and rapidly progressive disease. These patients tend to have worse overall outcomes, likely related to their aggressive underlying disease.”

Where does radiation fit into BT?

According to the 2024 report, “combination chemoimmunotherapy has typically been the form of BT that is used most often.” Targeted therapy is another option, the report said, although data is from “very small sample sizes.”

And then there’s radiation, which the report said is useful “particularly in patients with limited sites of disease or patients who are at risk for structural complications such as airway compromise or renal dysfunction.”

What do we know about radiation’s efficacy?

The first oral report on bridging radiation in CAR T-cell therapy only appeared in 2018, Plastaras said, followed by the first published report in 2019. Despite this fairly short time period, “we are certainly seeing a lot of new data,” Plastaras said.

He highlighted the newly released International Lymphoma Radiation Oncology Group (ILROG) study of radiation BT in conjunction with CAR T-cell therapy for relapsed/refractory B-cell lymphomas. The retrospective study of 172 patients at 10 institutions treated from 2018 to 2020 showed that 1- and 2-year progression-free survival (PFS) rate was 43% (95% CI, 36-51) and overall survival rate was 38% (95% CI, 30-45).

In a multivariable model, comprehensive radiation BT was linked to superior PFS than focal therapy (hazard ratio, 0.38; 95% CI, 0.22-0.63; P < .001).

“Comprehensive radiation was a very strong predictor for improved PFS, but we did not see was a huge dose effect,” said Plastaras, who coauthored the study.

What about toxicity?

Questions about other clinical matters were resolved prior to 2022, he said, when CAR T-cell therapy was used primarily in third line and later settings.

“Does radiation cause excess toxicities?” he asked. “A lot of the single-institution studies answered that, and I think most medical oncologists and hematologists are okay with this idea that radiation isn’t causing a lot of excess toxicities.”

As for whether radiation interferes with the effectiveness of CAR T-cell therapy, “the data to this point have demonstrated that probably not,” he said. “We’ve probably put that one to bed.”

What do we know about treatment timing?

“The timing question is still quite open,” Plastaras said. “How much time should there be between radiation and lympho-depleting chemotherapy? Is it better to put the radiation very close to the CAR T-cell [therapy] so this priming effect might happen, or can that happen weeks in advance? We don’t know the answers to those.”

According to Plastaras, researchers are still trying to understand the role radiation the consolidation period after CAR T-cell therapy. “If we wait for day-30 PET [scan], is that OK? Do we need to wait longer? Are we going to mess up the lymph nodes that have CAR T-cells floating around in them?”

What about doses and imaging?

There’s also a lack of insight into technical questions about radiation dose and fractionation. “The [radiation] volume question is one of key importance. Do we just do gross disease? Do we treat all the other small spots out there, and importantly, do we treat regional nodes or not? We get these questions all the time.”

The role of imaging is also unclear, he said, in terms of timing during and after bridging radiation therapy and after CAR T-cell therapy.

What do we need to learn about now?

Looking forward, Plastaras outlined what he called “version 2.0” questions for the evolving field: Can radiation rebulking decrease CAR-T cell toxicities? Will very low dose “priming” radiation affect outcomes? 

He highlighted other questions: Can radiation be part of a combined modality approach in limited stage relapsed/refractory disease? Should central nervous system lymphoma be treated differently? 

When will we get new guidelines?

According to Plastaras, Memorial Sloan Kettering Cancer Center Radiology Oncologist Brandon Imber,MD, MA, in New York City, is leading a new ILROG guideline project with the intention of publishing details in the journal Blood. “This is a work in progress,” Plastaras said. “Our target is 2025 to at least get something submitted.”

Plastaras had no disclosures.

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A rare cell in the lining of lungs is fundamental to the organwide response necessary to repair damage from toxins like those in wildfire smoke or respiratory viruses, Stanford Medicine researchers and their colleagues have found. A similar process occurs in the pancreas, where the cells, called neuroendocrine cells, initiate a biological cascade that protects insulin-producing pancreatic islet cells from damage.

Treating the airways of mice with an experimental drug that activates the repair pathway protected their airways from damage after infection with influenza or the virus that causes COVID-19. Conversely, animals in which the pathway was blocked experienced much more severe damage to their airways.

Activating the signaling pathway initiated by airway or pancreatic neuroendocrine cells in a similar way in humans might enhance the ability of firefighters and those with respiratory illnesses to avoid permanent lung damage, the researchers believe. They also suspect it could help prevent people with metabolic syndrome from progressing to diabetes.

“This whole signaling cascade both protects and regenerates vulnerable cells in the airway and the pancreas,” said Philip Beachy, PhD, professor of urology and of developmental biology. “If this circuit is disrupted, the damage is much worse — specialized airway cells are lost, and the stem cells can’t divide to repair the damage. We think it’s likely to be important in many other tissues in the body.”

Although the study was conducted in mice, there are tantalizing clues of a similar pathway in humans: People treated with a cancer drug that blocks the pathway are twice as likely as their peers to develop diabetes after their treatment.

“The association is highly significant and gives us early hints that activating this pathway might be protective for people with metabolic syndrome who are beginning to lose beta cell function,” Beachy said.

Beachy, who is the Ernest and Amelia Gallo Professor and a member of the Stanford Stem Cell Institute, is the senior author of the research, which was published online June 9 in Cell. Research scientist William Kong, PhD, is the study’s first author.

Neuroendocrine cells are less than 1% of the total number of cells in the cells that line the airway, which is made up of a type of tissue called epithelium. Some of them cluster together in what are called neuroepithelial bodies and play an important role in sensing oxygen levels and modulating immune responses in the lungs. But others, especially those in the tracheal airway, are solitary, nestled alone among other types of epithelial cells. It’s not been clear until now exactly what function these solitary neuroendocrine cells perform.

The hedgehog family

Beachy’s laboratory has focused on the function of a protein family called Hedgehog proteins since Beachy identified the first member in fruit flies in 1992. Members of the family are best known for their critical function in embryo patterning in early development, but they also aid in the rejuvenation of many types of tissue. Desert hedgehog is one of the least studied of the three family members (the others are Sonic hedgehog and Indian hedgehog).

Previous work in Beachy’s lab showed that stem cells in the epithelial lining of the bladder respond to a signal cascade initiated by Sonic hedgehog to regenerate the bladder lining after bacterial infection. They wondered if hedgehog proteins were involved in the repair of damage in other epithelial tissues like the airway.

When Kong used a technique called bulk RNA sequencing to search for genetic messages encoding any of the hedgehog family members in the cells of the trachea, they detected a faint signal for the Desert hedgehog protein, but not for the other two family members. When they engineered mice in a way that caused cells expressing the Desert hedgehog protein to become fluorescent, they saw that the solitary neuroendocrine cells were making the Desert hedgehog protein.

Further research showed that the Desert hedgehog protein leaves the epithelium and travels into the layer of tissue beneath the epithelium, called the mesenchyme. There, it triggers cells to begin producing another protein called Gli1. When the airway cells sense damage, Gli1 induces the expression of a protein called IL-6 that triggers stem cells in the epithelium called basal cells to begin dividing and specializing to repair the damage.

This crosstalk between tissue layers, which the researchers call epithelial-mesenchymal feedback, protects and regenerates specialized cells in the lung epithelium, including multi-ciliated cells that use their feathery arms to sweep particles and viruses out of the lungs and secretory cells that make mucus to trap unwanted invaders. In the absence of these cells, viruses and toxins can penetrate much more deeply into the lungs

Protective process

The entire process happens within hours of toxin exposure in a coordinated cascade that eventually includes even non-Gli1-expressing cells of the airway.

“At each stage, the signal is amplified until the entire trachea is impacted,” Beachy said. “This rapid response not only protects the epithelial cells from dying but it also activates a regenerative response.”

The consequences of impeding this protective message are severe.

“If this signal cascade is disrupted, the damage is much worse. Ciliated and secretory cells are lost, and the basal cells don’t divide. In fact, it’s all they can do to stretch out and try to cover the injured area,” Kong said.

Both Desert hedgehog and Gli1 are critical to the repair process. Mice unable to produce Desert hedgehog or Gli1 were much more sensitive to exposure to sulfur dioxide gas, which is an environmental pollutant and mimics the damage inflicted by other inhaled toxins. While control mice lost 85% of ciliated cells and 41% of secretory cells within 24 hours, mice lacking the protein lost 96% of ciliated cells and 88% of secretory cells during the same time.

Activating the hedgehog signaling pathway with a small molecule dramatically increased cell survival after sulfur dioxide exposure: 66% of ciliated cells and 82% of secretory cells survived in treated animals, versus 9.7% of ciliated cells and 43% of secretory cells in control animals.

Kong next tested the effect of the Desert hedgehog pathway activation on mice infected with influenza and the virus that causes COVID-19. Although no mice unable to make Gli survived more than five days after infection with influenza, all mice treated with the small molecule activator survived at least eight days after infection. Mice infected with the virus that causes COVID-19 that were unable to activate the Desert hedgehog pathway suffered extensive loss of ciliated cells in the airway.

Finally, the researchers turned their attention to the pancreas, which has a similar tissue organization as the airway. They found that the insulin-producing beta cells, which are a type of neuroendocrine cell, also make Desert hedgehog and that the organ exhibits the same epithelial-mesenchymal feedback loop with IL-6 to protect the vulnerable cells.

The researchers are now exploring whether and how the hedgehog pathway could be activated in humans to prevent lung damage in people exposed to airborne toxins or who are at risk for diabetes.

“We have reasons to think it might not be a good idea to activate the hedgehog pathway long term,” Beachy said. “We are considering how to stimulate the pathway in a targeted way, either delivering it to the airway with an aerosol or targeting it to the pancreas. And we have early hints it might be possible.”

Reference: Kong W, Lu WJ, Dubey M, et al. Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling. Cell. 2025;0(0). doi:10.1016/j.cell.2025.05.012

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