The SECURE project delivers its recommendations on clinical applications of alpha particle therapy

A major contributor to global mortality, cancer remains one of the most formidable health challenges of our time. According to global statistics from the World Health Organization (WHO), in 2022 there were an estimated 20 million new cancer cases and cancer was responsible for approximately 10 million deaths [1]. About one in five people will develop cancer in their lifetime, and the International Agency for Research on Cancer foresees an increase in the cancer burden by 77% by 2050 [2]. Focusing closer to home, data from the European Cancer Information System indicate that 2,7 million people are diagnosed with cancer in Europe each year and that this number is expected to increase to more than 3,24 million by 2040 [3].

The increasing incidence of cancer, globally and in Europe, can be attributed to both the aging and expansion of the population, alongside shifts in individuals’ exposure to risk factors. It further strains health systems, individuals and communities, underscoring the urgent need for innovative therapeutic approaches.

Traditional cancer treatments such as surgery, chemotherapy, and external beam radiation therapy have made significant strides, but they often come with significant side effects and limitations. Many cancers, especially metastatic forms, pose persistent challenges due to their ability to spread throughout the body. Targeted Alpha Therapy is such a new approach to cancer treatment.

Understanding Targeted Alpha Therapy

Targeted Alpha Therapy (TAT) utilises alpha-emitting radioisotopes attached to specific carrier molecules such as monoclonal antibodies or peptides. These molecules target cancer cells selectively, even if they are distributed throughout the body, recognising specific antigens on the cell surface. This targeting mechanism allows the molecules to adhere exclusively to cancer cells, like a puzzle piece fitting perfectly into its designated spot. In essence, the carrier taxies the alpha emitter directly to the tumour cell.

Alpha particles have high linear energy transfer (LET), meaning that they deliver a large amount of energy over a short distance, effectively damaging the double-stranded DNA of individual malignant cells beyond repair while sparing the surrounding healthy tissue. The precision of TAT offers a promising avenue to tackle metastatic cancers and other resistant forms that conventional treatments struggle to manage. By harnessing the unique properties of alpha particles, TAT aims to enhance treatment efficacy and minimise adverse effects, potentially transforming the landscape of cancer care by improving patient outcomes and quality of life.

Challenges of TAT

In 2013, radium-223 (Ra-223) became the first (and only, still) alpha therapy to gain approval for clinical use, leading the way for developing alpha-emitting therapeutic radiopharmaceuticals. Typically administered as radium-223 dichloride, its physicochemical properties make it naturally target hydroxyapatite and bone matrix. Used in the treatment of metastatic prostate cancer, this therapy has shown significant success by specifically targeting bone metastases where it delivers high-energy alpha particles directly to cancerous cells in the bones. However, the full clinical potential of alpha particle therapy has not been explored yet. Indeed, TAT is currently limited, both in terms of research and development and therapeutic use, by the availability of the desirable radionuclides. Several challenges must be addressed:

• Many alpha-emitting radionuclides are rare and difficult to produce in sufficient quantities for widespread clinical use. This rarity complicates the irradiation target manufacturing process, which is already complex and requires specialised knowledge and facilities. Additionally, the half-lives of these radionuclides can pose logistical challenges. Some alpha emitters have very short half-lives, necessitating rapid production, transportation, and administration to patients, which can be difficult to coordinate efficiently.
• The nuclear infrastructure necessary to support TAT is scarce. Existing facilities are often insufficient to meet the growing demand, and establishing new, innovative nuclear systems for efficient and safe production is a complex and costly endeavour. Developing these systems involves not only significant financial investment but also extensive time and regulatory approval processes.
• On the clinical side, hospitals face challenges in implementing TAT safely. Safety guidelines for handling and administering these potent radiopharmaceuticals are not yet well established, creating a barrier to widespread clinical adoption. Healthcare providers must be adequately trained, and facilities must be equipped to manage these therapies safely.

How the SECURE project can help

The SECURE project addresses these challenges by focusing on the sustainability and safety of medical isotope production in Europe. The importance of the project’s endeavour has recently been recognised by the Council of the European Union, which cited SECURE as an example of an initiative towards a stable supply of medical radioisotopes [4, 5]. Indeed, the consortium’s primary objective is to establish reliable production routes and irradiation targets for both existing and new alpha emitters, ensuring a consistent supply of radionuclides for clinical applications. By efficiently utilising current resources, the consortium seeks to significantly advance the development and production of new radionuclides.

A key focus of SECURE is to develop robust and scalable production methods for crucial radionuclides used in nuclear medicine, encompassing both diagnostic and therapeutic applications. The project is dedicated to exploring traditional reactor-based routes as well as innovative accelerator-based methods. This includes identifying and evaluating production techniques for alpha emitters like Ac-225 and Pb-212 as well as beta-emitters such as Lu-177, Tb-161, Au-199, and Ag-111, to create a sustainable production chain.

Additionally, SECURE is committed to improving the design of irradiation targets and radioisotope generators to enhance the practical application of these isotopes in clinical settings. By selecting isotopes vital for the success of nuclear medicine and through dedicated research and development efforts, SECURE intends to support the transition from laboratory-scale production to large-scale implementation, ensuring the availability of essential radionuclides for therapy and diagnostics.

Furthermore, the project seeks to identify the most appropriate clinical applications for alpha radionuclides and provide recommendations for clinical trials that will assess treatment efficacy. This will ensure that the clinical potential of these innovative therapies is fully realised, ultimately improving patient outcomes.

SECURE recommendations on clinical applications of TAT

The Istituto Romagnolo per lo Studio dei Tumori Dino Amadori – IRST led the literature review of current clinical applications of new alpha-emitting radionuclides that were conducted for the development of the recommendations. Five SECURE partners (NNL, IMAGO-MOL, UMCL, NCBJ) worked collaboratively over 15 months during which they selected 7 alpha radionuclides, which were identified and chosen based on their clinical significance. The process followed a rigorous methodology and included interrogating major databases using specific keywords that are related to alpha-emitter therapy, limited to articles in English. For each of the selected alpha emitters, the resulting report explores detailed information about physics characteristics and radiochemistry features, as well as preclinical and clinical studies. The final document also includes potential information for future perspectives and when available the knowledge and experiences of the SECURE consortium involved in the project.

Thanks to this collaborative work, the SECURE partners provide seven recommendations to establish the therapeutic efficacy of alpha-emitting radionuclides and support the development of TAT:

• Alpha-emitting radionuclides show great promise in reported clinical trials, which have led to the initiation of a large number of clinical trials currently ongoing investigating these treatments. This demonstrates this is an area of great potential for patient benefit.
• For clinical trials to progress utilising alpha-emitting radionuclides access to a secure supply of these radionuclides is essential and so needs to be supported. The existing portfolio of trials has been driven as much by access to radionuclides of sufficient quality and quantity for GMP radiopharmaceutical production, and scalability of supply (which includes restrictions due to half-life) as it has by the radionuclide properties (such as chemical properties, decay scheme).
• Many radionuclides considered in this review do not decay into a stable element but instead decay to radioactive progeny. The off-target effects of these are very important to consider for dosimetry and radiation safety, and this should be built into clinical trial design.
• Chelating agents or pre-cursors for radiopharmaceuticals should be selected that are optimised for the alpha-emitting radionuclide being used, to ensure stability and minimise off-target effects due to dissociation of “free” radionuclide. However, due to the large recoil energy created upon alpha emission, if there is radioactive progeny this will always be released from the targeting moiety. This can happen both during transport to the hospital and after administration of the radiopharmaceutical and the impact of the ratio of these should be considered during trial design.
• Dosimetry measurements should be an important part of clinical trials using alpha-emitting radionuclides, and standardised methodology should be used.
• To optimise the benefits from the ongoing clinical trials, there should be standard ways to report trial results, and standardised protocols within the trials.
• Currently a lack of clinical trial data in this area limits the recommendations that can be made about the alpha-emitting radionuclides that are most effective for a specific disease type/ stage. Further clinical trials should be supported in this area, due to the promise that early trials have shown, and these should also include sample collection, to allow reverse translation and further understanding of the radiobiology.

For more information on the SECURE project, visit the official website.

References

1. World Health Organization (2022). Cancer. [online] Available at: https://www.who.int/news-room/fact-sheets/detail/cancer.

2. International Agency for Research on Cancer (n.d.). Cancer Tomorrow. [online] Available at: https://gco.iarc.fr/tomorrow/en.

3. European Cancer Information System (2020). Incidence and mortality 2022. [online] Available at: https://ecis.jrc.ec.europa.eu/explorer.php?.

4. Council of the European Union (2024). Radioisotopes for medical use: Council approves conclusions. [online] Available at: https://www.consilium.europa.eu/en/press/press-releases/2024/06/17/radioisotopes-for-medical-use-council-approves-conclusions/

5. Council of the European Union (2024). Council conclusions on the security of supply of radioisotopes for medical use. [online] Available at: https://data.consilium.europa.eu/doc/document/ST-9912-2024-INIT/en/pdf

Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Atomic Energy Community (EC-Euratom). Neither the European Union nor the granting authority can be held responsible for them.