In 1953, a physician named RH Mole published a paper in the British Journal of Radiology describing a surprising phenomenon he called the “abscopal effect.”1 While documenting the shrinkage of tumors that were directly irradiated, Dr. Mole noticed that even untreated tumors, located in lesions beyond the scope of treatment, also shrank. How could the radiation treatment possibly affect these “out of scope” tumors?
Dr. Mole’s 1953 paper was one of the earliest published observations suggesting a possible interaction between radiation and the immune system in metastatic cancer. More than two decades later, a handful of physician-scientists had a hunch that radiotherapy’s effects might be tied to immune competence. Working mostly in animal models, they investigated the idea, but momentum stalled until the 2010s. That lull ended with the rise of immunotherapy, when studies began exploring radiation’s role in combination treatment approaches.2
New evidence suggests that in some patients with blood cancer, adding radiation to immunotherapy, such as CAR-T or checkpoint inhibitors, seems to extend benefits beyond the local treatment site, improving overall outcomes in patients, though why that happens remains unclear.
Chasing a unicorn
“The abscopal effect is kind of a unicorn,” said Austin Sim, MD, JD, a radiation oncologist at The Ohio State University.
“We’ve seen it in a handful of case reports. It’s very rare and not something we’ve been able to reproduce systematically.”
One possible mechanism is immune priming: the idea that radiation changes the tumor microenvironment in ways that make immunotherapies more effective.
“There’s something about the immune microenvironment and the interaction between immunotherapies and radiation that we still don’t quite understand in terms of how to trigger it,” said Dr. Sim. “While we have intriguing preclinical data, we don’t yet have significant evidence for immune priming in a clinical setting.”
Dr. Sim, while stressing that the hypothesis remains unproven, cited neoantigens as one potential mechanism by which this might work. In this account, radiation triggers an immune response and amplifies the effects of immunomodulatory therapies via the release of neoantigens, which make tumors more immunogenic, thereby triggering a T-cell response even in untreated areas.
Another possibility is that the improved outcomes seen with radiation and immunotherapy combinations have nothing to do with the immune system. Instead, they may simply reflect better disease control, specifically better local control of high-risk tumors.
Whatever the explanation turns out to be, the uncertainty is driving new lines of research and prompting some clinicians to revisit how radiation is used in patient care.
New evidence for immune priming
“For a long time, probably up until around 2000 or 2010, a lot of people didn’t believe it was real,” said Mohammad Khan, MD, PhD, a radiation oncologist who specializes in blood cancer at Emory University, describing the abscopal effect. “What is the mechanism? What is the biology? How could we enhance it? That’s always been the Holy Grail for many in radiation oncology and biology, and now, more specifically, radiation immunology.”
Dr. Khan’s lab, in collaboration with immunologist Rafi Ahmed, PhD, developed early mouse models beginning in 2011 to investigate how radiation might activate a subset of stemlike CD8-positive T cells. These preclinical studies suggested that radiation could boost the T-cell priming in a way that might complement checkpoint blockade.
Building on that foundation, Dr. Khan led a pilot study3 in patients with penta-refractory multiple myeloma, combining low-dose radiation with the PD-1 inhibitor pembrolizumab.
The findings, published in Lancet Haematology in 2024, offered early clinical support for his hypothesis first tested in mice that radiation could potentially augment immune activity when paired with immunotherapy to improve outcomes.
“There were two novel aspects of the study which I think really helped us distinguish from other designs,” Dr. Khan said about the 2024 paper. “First, we prespecified what we called ‘abscopal responses,’ defined as radiographic improvement on imaging at a non-irradiated, distant site, and we were able to document those improvements. Secondly, and I think more importantly, we were able to look at blood biomarkers. Four of five patients who showed abscopal response also had CD4+ and CD8+ responses.”
“It was encouraging and safe, but it was a small study,” he noted.
Dr. Khan’s research group is currently planning a new trial combining radiation, PD-1, and proteasome inhibitors.
Other researchers are currently testing how lower-dose approaches might modulate the immune system. Trials at Moffitt Cancer Center in Tampa, Florida, Memorial Sloan Kettering in New York, and the University of Texas MD Anderson Cancer Center in Houston are now exploring how radiation might be tailored by dose, location, and timing to complement immunotherapy.
Radiation can also provide a benefit without ‘all the fancy immune stuff’
Timothy Robinson, MD, PhD, an associate professor of therapeutic radiology at Yale University, remains excited about the idea of radiation being used to facilitate immune priming, but noted that researchers have not yet been able to show it works in humans.
The idea that radiation somehow primes the immune system reflects a “vaccine model,” according to Dr. Robinson, and he isn’t necessarily convinced that it is the answer.
“The kind of vaccine model, if you will—there’s a lot of preclinical data, like mouse models—but there are many differences between humans and animal models of both
tumors and the immune system, and no one has made it work in humans,” he said. “We don’t have any data on that front, and in solid tumors, we’ve tried using radiation as “vaccine” until we’ve been blue in the face. This is why I don’t necessarily believe that the vaccine model, as an overall strategy, is where it’s at. I think we need more research to understand why these approaches have failed before we have a chance of making that strategy work in the clinic. I think it is fantastic that people are exploring this, but we aren’t there yet.”
Instead, he supports the more pragmatic approach of targeting areas with radiation where CAR-T is most likely to fail.
In a study that investigated patterns of failure in lymphoma, Dr. Robinson and a team of investigators reported that in patients who are treated with CAR-T therapy, 85% or more of the treatment failures involved local sites of disease progressing on treatment. In other words, he explained, the disease progresses exactly where it started.4
“Among all patients with aggressive lymphomas going into CAR-T, roughly a third of patients only experience progression at an existing site of disease,” he explained. “Lymphoma is very sensitive to radiation, which raises the question—if we had treated all sites of disease in one of these patients—could we have prevented treatment failures and saved more lives?”
Studies to date have casted doubt on the ability to reliably induce the abscopal effect in humans, according to Dr. Robinson. However, if controlling relapse is simply a matter of targeting high-risk areas with radiation, there could be a far more straightforward solution.
“If we put aside the fancy immune stuff for a moment, I think there are more direct, less hypothetical strategies that might work,” he said. “If we can just neutralize the place where this thing’s going to come back, then maybe we can cure some people who otherwise would have died from their disease. That’s where I think radiation can already help to improve outcomes, without having to invoke currently unproven, albeit intriguing, abscopal-type phenomena.”
He added, “We also know that large volume disease, often characterized by bulky, hypoxic tumors, are likely incredibly immunosuppressive. Perhaps radiation can help the immune system after all—not by a direct vaccine mechanism—but by killing large tumors with immunosuppressive environments that might otherwise have stopped CAR-T cells in their tracks.”
Dr. Robinson gave a concrete example of how these localized benefits could improve the outcomes of subsequent treatments.
“If you’ve got 100 people going into CAR-T, 20% will have purely local failures,” he said. “That means you could potentially increase cure rates by 20% with radiation based on improvements in local control alone.” He notes, “However, every case is unique, and not all patients are good candidates for radiation. Being evaluated by someone who has treated a lot of these cases is critical.”
Radiation as a bridging therapy
While the idea of immune priming is alluring at the theoretical level, bridging therapy, a more immediate clinical practice, is another domain in which researchers are asking whether radiation can play a role in making subsequent treatments more effective.
In the case of CAR-T treatment, the process typically requires waiting several weeks, since it involves collecting the patient’s own T cells, genetically modifying them to express a CAR, expanding the engineered cells in a manufacturing facility, and then infusing them back into the patient.
Often used for palliative purposes and to control disease during this waiting period, bridging therapy was not originally designed to trigger immune effects, but new research is nudging it in that direction.
“We started using radiation as a bridge because it was a question of do something or do nothing while waiting for CAR-T manufacturing,” Dr. Sim said.
In retrospective analyses, some researchers began to notice that patients who received radiation before CAR-T appeared to do better than those who didn’t, although they have been unable to determine whether that improvement stems from better disease control or a deeper immune interaction. At the 66th American Society of Hematology Annual Meeting and Exposition, a team led by Hamish Scott, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, reported on a retrospective analysis of patients with relapsed/refractory large B-cell lymphoma (LBCL) who received radiation before CAR-T therapy (axicabtagene ciloleucel). The investigators found that the radiated patients had better outcomes, even after adjusting for tumor burden and other risk factors.
“When we radiated bulky or symptomatic sites as bridging before CAR-T, the multivariate analysis still showed those patients did significantly better,” Dr. Scott said.
In particular, the results showed that progression-free survival at 12 months was 75% in the group that received radiation therapy versus 49% in the group that received systemic-based bridging therapy, representing the standard of care.
In the conclusion of the paper, Dr. Scott and colleagues cautioned that because their analysis was retrospective, “it was not possible to separate the impact of disease distribution that is amenable to radiotherapy from the impact of radiotherapy itself.” However, the paper concluded that given the favorable outcomes they observed, “radiotherapy should be considered as part of the bridging strategy wherever feasible.”
The evidence isn’t strong enough to draw firm conclusions, Dr. Scott said.
“The question is, are they doing better just because their disease was reduced before CAR-T or is there a real immunologic effect?” Dr. Scott said.
‘Something is happening’
All this new research activity on immune priming and bridging therapy is invigorating the field of radiation oncology, according to Dr. Sim.
“It’s definitely an exciting time to be in the field of managing patients with hematologic malignancies with radiation,” he said. “I view any new systemic therapy that comes out as another opportunity to figure out how radiation can make that work better, especially now with modern treatment planning and the way we’re doing radiation, which is a lot safer and a lot less toxic, especially compared with a lot of traditional cytotoxic chemotherapy.”
Dr. Sim also said that there is still much to learn.
“There are a lot of variables we still haven’t figured out how to optimize,” Dr. Sim said. “Radiation isn’t a monolith. It’s a dose-dependent tool.”
For the scientists pursuing the benefits of radiation treatment, the irony might not be lost on them that the object of their investigation is not a glamorous new scientific discovery but an old technology whose properties were first investigated by Marie Curie and others in the 1890s. And yet here they are in the 21st century continuing to investigate this “old” modality alongside the most cutting-edge therapies clinicians can offer patients.
Science is, at its core, the pursuit of truth through empirical observation. But sometimes the signal is too faint, the noise too loud, or the framework too narrow to register what might be there. We circle something without quite capturing it, and that, too, is part of the process. It may turn out to be nothing at all, or a scientific breakthrough may lie just around the corner.
“We’re not mice, but the biology says something is happening, and patients need us to chase it,” Dr. Khan said.
References
- Demaria S, Formenti SC. The abscopal effect 67 years later: from a side story to center stage. Br J Radiol. 2020;93(1109):20200042. doi:10.1259/bjr.20200042
- Van Limbergen EJ, De Ruysscher DK, Olivo Pimentel V, et al. Combining radiotherapy with immunotherapy: the past, the present and the future. Br J Radiol. 2017;90(1076):20170157. doi:10.1259/bjr.20170157
- Khan MK, Nasti TH, Qian JY, et al. Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA [published correction appears in Lancet Haematol. 2024 Aug;11(8):e560. doi: 10.1016/S2352-3026(24)00221-7.]. Lancet Haematol. 2024;11(7):e510-e520. doi:10.1016/S2352-3026(24)00105-4
- Figura NB, Robinson TJ, Sim AJ, et al. Patterns and predictors of failure in recurrent or refractory large B-cell lymphomas after chimeric antigen receptor T-Cell therapy. Int J Radiat Oncol Biol Phys. 2021;111(5):1145-1154. doi:10.1016/j.ijrobp.2021.06.038
- Scott H, Dowling M, Garcia D. Bridging radiotherapy to axicabtagene ciloleucel (axi-cel) is associated with favourable outcomes for large B-cell lymphoma (LBCL) in third-line and beyond: an Australian single-centre real-world experience. Abstract #4511. Presented at the 66th American Society of Hematology Annual Meeting and Exposition. San Diego, California.
