Alpha-particle therapy for neuroendocrine tumors: A focused review

Introduction

In the early 1990s, peptide receptor radionuclide therapy (PRRT) was developed using ¹¹¹In-DTPA-octreotide (Octreoscan) due to its properties of releasing secondary β-radiation to cause targeted DNA tumor damage. They had reasonable response rates, but responses were not durable (1). β-emitting ⁹⁰Y was the first second-generation radionuclide used for PRRT with good symptomatic and objective response rates but a significantly increased risk of permanent kidney damage due to tubular damage and microangiopathy (2). Subsequently, the safer β-emitting ¹⁷⁷Lu was developed, and over the last decade, ¹⁷⁷Lu-DOTATATE (Lutathera) has become the most widely used PRRT and is licensed by both the Food and Drug Administration (FDA) and European Marketing Authority (EMA). However, despite the success of ¹⁷⁷Lu-DOTATATE, especially following the results of the NETTER-1 trial, patients invariably relapse in 2–3 years following PRRT. The recent NETTER-2 trial has also shown the efficacy of PRRT for high-grade well-differentiated tumors (3). Many strategies have been investigated to improve the effectiveness of PRRT, but targeted α-particle therapy (TAT) has gained the most attention over the past few years. We summarize and update the results of our recent review, to which we refer for a more in-depth analysis of earlier studies (4).

Physical and Radiobiological Properties of α- and β-particles

1. α-particles

   Alpha-particles comprise two protons and two neutrons. They are produced in the process known as α-decay. As shown in Figure 1, as they have high particle energy, high linear energy transfer (LET), and a short therapeutic range (c.100μ), they cause highly-selective double-strand breaks (DSBs) in the DNA of cancer cells, but without affecting surrounding normal cells (4). Alpha-particles have a higher relative biological effectiveness for the same absorbed radiation dose.

2. β-particles

   The β-particle, an energetic electron, is created by β-decay, a process in which, in an unstable nucleus, a neutron is converted to a proton with the release of an electron. They have comparatively low particle energy and a low LET but a high therapeutic range (c.1mm). Due to these properties, many more β-particles are required compared with α-particles for a similar absorbed dose. They are also more likely to cause single-strand breaks (SSBs) than DSB and more likely to affect the surrounding normal cells (4).

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Figure 1 and Table 1 depict the major physical and radiobiological differences between α- and β-particles.

TAT and Neuroendocrine Tumors

²²³Ra-chloride (Xofigo) was the first licensed α-emitting radiopharmaceutical used in the treatment of prostate cancer with bone metastases. Subsequently, several α-emitting radiopharmaceuticals, such as ²²⁵Ac, ²¹³Bi, and ²¹²Pb, have been used clinically in the treatment of neuroendocrine tumors (NETs) (5).

1. ²²⁵Ac

   ²²⁹Th serves as the main source of ²²⁵Ac and its parent ²²⁵Ra. ²²⁵Ac has a half-life of 9.9 days and a 6-step process decay scheme to stable ²⁰⁹Bi. During this process, a total of four α-particles (of 6–8 MeV energy each) and three β-particles are emitted. A half-life of 10 days and high overall α-emission energies of 27.5 MeV render ²²⁵Ac a potentially appealing radionuclide for TAT (4).

2. ²¹³Bi

   Being a daughter of ²²⁵Ac, ²¹³Bi follows a similar decay scheme. It has a half-life of 45 min and produces one α-particle but no β-particles, with a mean energy of 8.3 MeV. It has not been used extensively due to its short half-life, which would necessitate on-site labeling (6, 7).

3. ²¹²Pb

   ²¹²Pb produces an α-emitting daughter ²¹²Bi that produces a single α-particle with a mean energy of 7.8 MeV. ²¹²Pb is a daughter product from the decay of ²²⁸Th: ²¹²Pb has a half-life of 10.6 h, which allows for ease of radiolabelling and administration (8).

Preclinical Animal Studies using TAT in SSR-expressing Tumors

All three radionuclides (²¹³Bi, ²¹²Pb, ²²⁵Ac) discussed earlier have been studied in animals in preclinical trials. ²¹³Bi-DOTATOC and ²¹³Bi-DOTATATE have been investigated in a rat pancreatic carcinoma model and mice bearing somatostatin receptor (SSR)-expressing NETs, respectively (9, 10). In both studies, investigators found reduction and delay in tumor growth. They reported no significant renal or bone marrow toxicity (9, 10). Stallons and colleagues investigated ²¹²Pb-DOTAMTATE in a rat pancreatic cell line, where they found increased median survival compared with the control group. The survival was further improved by adding 5-fluorouracil. They observed reversible bone marrow toxicity at a dose of 740 kBq of ²¹²Pb-DOTAMTATE (11). ²²⁵Ac-DOTATOC and ²²⁵Ac-DOTATATE were investigated in mice (12, 13). ²²⁵Ac had a mean energy 70 times higher compared with ¹⁷⁷Lu. ²²⁵Ac-DOTATATE at a dose of <111 kBq was found to be safe and was associated with a significant delay in tumor growth compared with controls (12, 13).

Clinical Studies using TAT in NETs

Ongoing Clinical Trials

Currently, a small number of clinical trials are underway evaluating the effects of ²¹²Pb and ²²⁵Ac in patients with SSR-2-expressing NETs. There is a commercial phase II study (NCT05153772) on ²¹²Pb-DOTAMTATE (AlphaMedix) to explore treating patients with SSR-2-expressing NETs refractory to standard therapies. Primary outcome measures are overall response rate and adverse events. This trial is expected to report later in early 2025 (4, 19). Another ²¹²Pb-SSA TAT has been investigated by Perspective Therapeutics (²¹²Pb-PSC-PEG2-TOC) (VMT-α-NET) and is undergoing early clinical trials. In this trial, investigators will establish a recommended phase II dose (RP2D) followed by a phase IIa dose-expansion cohort evaluating efficacy using the RP2D (19). RayzeBio Inc. is assessing the efficacy of ²²⁵Ac-DOTATATE (RYZ101) in multicentre clinical trials [ACTION-1 clinical trial (NCT05477576)] after progression through ¹⁷⁷Lu-SSA in SSR-expressing GEP-NETs. In Part 1 of the trial (phase Ib), they concluded that 120 kBq/kg should be the recommended phase III dose. The study will proceed to Part 2 (phase III) with a comparison of RYZ101 at 120 kBq/kg with “standard of care” in patients with GEP-NETs with disease progression following prior ¹⁷⁷Lu-labeled SSAs (4, 19). An investigator-run phase I trial conducted by Fukushima Medical University in Japan is studying ²¹¹At-meta-astatobenzylguanidine (MABG) in patients with malignant phaeochromocytoma or paraganglioma. MABG targets adrenergic tissue through the norepinephrine transporter; the dose escalation trial will determine safety, MTD (maximum tolerated dose), and RP2D (19).

Limitations, Challenges, and Future Directions

As these isotopes used for cancer treatment decay relatively rapidly, are heavily regulated, and are expensive to make, the use of TAT in a routine clinical practice is highly challenging. For example, the use of ²¹³Bi is limited, given its short half-life and need for onsite labeling. Additionally, its production, purification, chelation, shipping, and administration must be highly choreographed to be successful. Any disruption in the supply chain can leave a patient missing a dose. Despite these challenges, several companies worldwide are developing ²¹²Pb generators, which are also readily available through private and government sources. It may become the most widely used α-emitting radionuclide (8). However, regulatory hurdles such as regulatory compliance on production, transportation, disposal by nuclear regulatory agencies, radiation containment protocols, complex study designs, stricter pharmacovigilance, waste disposal, and environmental impact makes it challenging to develop and implement TAT (20). These hurdles could be overcome by diversification of production sources, international collaboration, early engagement with regulatory bodies, automated manufacturing systems, improving targeting agents, advanced dosimetry models, international standardization, and eco-friendly disposal methods (21).

While the studies discussed above have shown promising results, it should be considered that reporting of the response criteria across the different studies has varied. Another major concern is regarding hematological and renal toxicity associated with TAT. However, in a recent meta-analysis, the incidence of toxicities was uncommon, in the range of 2.1% to 3.4%. Despite this rarity, due to the lack of robust evidence on safety profiles, this will necessitate careful monitoring for such toxicities in patients receiving TAT therapy (22). Detailed previous treatment history with other radionuclide therapy, such as β-emitting therapy with ¹⁷⁷Lu, should also be considered before offering TAT to patients as it increases the risk of toxicity with TAT (23). Dosimetry (calculating the dose of radiation delivered to organs and tumors) is difficult by macrodosimetry with current alpha emitters. The majority of radionuclides, which emit α-particles, emit no or little gamma irradiation or positrons for imaging with SPECT or PET, and there is heterogeneous antigen expression among cancer cells (19). However, Singh and colleagues have calculated image-guided dosimetry and response assessment using ²¹²Pb-VMT-α-NET in a patient with a metastatic NET; the patient received a cumulative radiation dose of 3.9 Gy to the target lesions with the dose for all critical organs remained within acceptable limits (24). Newer microdosimetry techniques of TAT, as a function of the source-target configuration, cell geometry, other biological factors, and cell sensitivity, should help to overcome these hurdles (25).

Conclusions

TAT is an exciting and promising therapeutic modality for SSR-expressing NETs. TAT has potential advantages over β-emitting therapy due to the high energy and short path length of α-particles and overcoming radio-resistant conditions, such as hypoxia. Although TAT-related long-term hematological toxicity data are not available, currently available toxicity data suggest low acute grade 3/4 hematological toxicities at defined administered activities. The kidney may prove to be a critical organ for TAT due to the high LET of TAT and associated renal tubular damage. However, in due course, other ways of improving on α-particle therapy, such as have been suggested and trialed for standard β-emitting PRRT, including the use of chemotherapy or PARP inhibitors, may render it even more effective. These are exciting times in the realm of theranostics, and interest in neuroendocrinology, now subsuming all neuroendocrine cells in the body and the pituitary, builds on the fundamental work of Sy Reichlin.

Acknowledgments

The authors acknowledge our outstanding debt to Dr Seymour Reichlin for his inspiration and devotion to research in the field of neuroendocrinology. Dr Reichlin was one of the founders of the “new” science of neuroendocrinology. Born in 1924 to Russian immigrants to New York, he sadly lost his sister to an endocrine-secreting tumor of the pancreas, probably a VIPoma, an important albeit rare type of tumor regarding which our brief review is relevant. He started his medical training at Washington University and the University of Rochester, becoming fascinated by Selye's concept of stress. However, the seminal moment in his career was his attendance at a lecture by Geoffrey Harris, which stimulated him to move to London in 1952 and work with Harris to establish the neural-hypothalamic – control of the pituitary, initially in terms of thyroid function. In subsequent work back in New England, he showed that the hypothalamus contained growth hormone and prolactin-releasing factors, all eventually chemically identified by the Nobel Laureates Roger Guillemin and Andrew Schally. He must therefore be considered as the “father” of neuroendocrinology and one on whose superb foundations we now rely for medical practice.

Author Contributions

A.B.G. conceived the review topic. K.M.S. drafted the initial manuscript, tables, and images. S.N. and A.B.G. reviewed, edited, and supervised the work. No related work is under consideration elsewhere. All authors revised and approved the final version.

Funding Sources

This article was not funded by external sources.

Authors Disclosures

The authors declare no conflict of interest.