Neutron Capture Therapy: The Promise of Novel Agents and Medical Facility-Based Neutron Sources

Neutron capture therapy (NCT) is based on nuclear capture and fission reactions that occur when an appropriate isotope is irradiated with low-energy (thermal) neutrons. Therefore, NCT for cancer treatment requires both a high flux neutron source and compounds capable of neutron capture itself or a molecule or system of delivering neutron capture isotopes selectively to tumor cells or their microenvironment. Although other isotopes with a relatively high probability of capturing neutrons (such as gadolinium-157, lithium-7, sulfur-33, and uranium-235) have been proposed as potential alternatives, only boron-10 ( ¹⁰ B) has been used in clinical trials and the treatment modality had been called boron neutron capture therapy (BNCT). ¹

The theoretical promise of NCT, that is, the potential of eradicating individual cancer cells that have spread within normal tissues without causing any adverse effects, prompted multidisciplinary teams of physicists, chemists, radiobiologists, and physicians to test this hypothesis since the early 1950s, when the first clinical trial was carried out at Brookhaven National Laboratory in Upton, NY. Unfortunately, the subsequent efforts in Argentina, Czech Republic, Finland, Italy, Sweden, and the United States were not successful in improving clinical outcomes. More recent efforts from Japan are described by Matsumura et al ² and Kondo et al. ³

In 2022, the U.S. National Cancer Institute (NCI) organized an international workshop on NCT. Publications included in this issue of Cancer Biotherapy and Radiopharmaceuticals describe recent developments as presented at this workshop. More information on the workshop, including recordings, can be found here. ⁴

In the past, nuclear reactors located in research institutions were used as epithermal neutron sources. The cost of the maintenance and often remote location of such facilities made clinical research very difficult. Recent technological advances have led to relatively small accelerator-based neutron sources that may be located in medical centers. Several commercial companies provide NCT installations with footprints and costs comparable with proton therapy facilities. This may offer new opportunities for research. Many accelerator-based NCT facilities have been installed or are being planned around the world. ⁵ Porra et al, for instance, presented their experience with the transition from nuclear reactor-based to proton accelerator-based NCT in Finland. ⁶

A major challenge of NCT is the delivery of a sufficient concentration of neutron capture agents selectively to cancer cells. ¹⁰ B-boronophenylalanine, the boron delivery agent tested in previous clinical trials, is still used in Japan. The mechanisms of its endocytosis have been studied and may be modulated to improve ¹⁰ B accumulation in tumor cells. ⁷ Furthermore, its distribution can be monitored by PET, potentially enabling proper patient selection. ⁸

Installation of new accelerator-based NCT systems has elevated interest in new approaches to tumor-specific delivery of boron and other neutron capture agents. These efforts might be facilitated by computational modeling studies for developing new tumor-targeting molecules. ⁹ A new generation of promising boron carriers include icosahedral boron clusters attached to peptides, proteins, porphyrin derivatives, dendrimers, polymers, and nanoparticles, or encapsulated into liposomes that may improve NCT. ¹⁰ Other neutron-capture nuclides emitting radiation with relatively longer range in tissue may be combined with ¹⁰ B to eradicate large heterogenous tumors. ¹¹ Several animal tumor models have been developed or adapted to test the new NCT compounds in preclinical settings. ^12,13

One of the commercial providers of radiotherapy treatment planning systems offers a system for BNCT that was shown to provide accurate estimates of all BNCT dose components for the clinically relevant boron concentrations. ¹⁴ Such systems, combined with noninvasive monitoring of boron distribution in individual patients and novel dosimetry methods, might allow individualized dosimetry-based treatment planning to improve the safety and efficacy of NCT. ^15,16

Careful clinical investigation with detailed examination of pharmacokinetics, possibly based on theranostics, ¹⁵ might allow to optimize the timing of drug and neutron treatment. Utilization of clinic-based neutron sources and appropriate phase clinical trials will provide key next steps toward defining how the theoretical benefits of NCT will translate into patient outcomes. ^17,18