Neuroendocrine tumors (NETs) are a rare type of tumor that develop from neuroendocrine cells. They can appear anywhere in the body, but most often occur in the gastroenteropancreatic (GEP) tract or the lungs. For localised NETs, surgery is the standard treatment. Chemotherapy and targeted drug therapy are typically used for metastatic NETs, though their slow growth makes these treatments less effective.

Peptide receptor radionuclide therapy (PRRT) offers a promising option for advanced metastatic NETs. PRRT is a targeted therapy using a peptide linked to a radionuclide that emits radiation to kill tumor cells. This peptide specifically binds to the somatostatin receptor subtype 2 (SSTR2), which is highly expressed in neuroendocrine tumor cells.

Image source: Cancer Research UK (2002) All Rights reserved. Cancer Research UK is an independent organisation not linked to NRG PALLAS. 

Erasmus MC has more than 20 years of experience in developing compounds for PRRT, such as Lutathera, now used in regular treatment of NETs. Despite these advancements, there is significant room for optimisation, as current treatments only cure about 4% of patients and only 20-30% of the patients are stable and progression-free. Some patients do not respond to the treatment at all.

Targeted Alpha Therapy could be a logical step forward to improve patient outcomes worldwide, according to Yann Seimbille, Associate Professor at Erasmus MC. “We have been interested in using alpha emitters for quite some time. One of the projects we had in mind involved using Actinium-225 for the treatment of NETs. While Actinium-225 has its advantages, it also has drawbacks, such as toxicity. This issue may be less pronounced with Lead-212.”

Erasmus MC now has a fully GMP lab to prepare compounds for TAT. “Erasmus MC has always been focused on the therapeutic application of nuclear medicine. And Lead-212 definitely has interesting characteristics, but it is barely available. Through FIELD-LAB, we had a chance to get our hands on this attractive radionuclide”, says Seimbille.

FIELD-LAB was founded in 2018, with NRG PALLAS taking the lead in forming a consortium comprising leading academic and industrial partners to speed up the development and market launch of new nuclear drugs for cancer treatment. “Quite some years ago, when the FIELD-LAB project was just an idea, we were approached by NRG PALLAS if we were willing to be part of this consortium”, Seimbille explains. “For us, it was a great opportunity to be involved, bringing new radionuclides into the game, especially radionuclides for therapy.”

Due to the overall shortage of Lead-212, obtaining sufficient quantities for any study is a challenge. But through collaboration, the team succeeded in producing this significant isotope. “We developed our method for the production of Lead-212, together with the Erasmuc MC”, says Yulia Buchatskaya, lead scientist at NRG PALLAS. “They faced challenges, and so did we. Initially, we encountered issues with the purity of our Lead-212 and had poor labeling yields. However, through collaboration, constant feedback, and discussions on potential solutions, we eventually managed to refine our process and produce a stable, pure product.”

The team began in a small-scale R&D laboratory with activities only large enough to do some minor labelling. Then they successfully upscaled to produce batches for preclinical research. Now Buchatskaya is aiming to further upscale production. She explains, “We are currently in the process of making the procedure robust and testing the equipment that will be housed in the hot cells. In a later stage, the process will be automated and compliant with GMP regulations, enabling the safe injection of Lead-212 into patients.”

The strength of the collaboration has been a key factor in progressing the project. Seimbille is very pleased with the collaboration, stating, “The collaboration has always been friendly and promising. We have been in a mindset of trying to help each other, making it a win-win situation.” In addition to advancing the process, securing funding to take this research to the next level is a key priority. Discussions on this topic between NRG PALLAS and Erasmus MC are currently underway.