National clinical translation of antibody-based molecular radiotherapy of advanced cancers
Targeted molecular radiotherapies can knock out metastases
A new form of radiation therapy – molecular radiation therapy – can be used to irradiate and kill metastatic cancer. A consortium of researchers from Swedish universities is now developing new types of molecular radiation therapy, with the hope of finding treatments for cancers where the prognosis is currently very poor.
Treating metastatic cancer using conventional radiotherapy – where radiation is directed at the tumour from outside the body – is difficult, because the metastases can be numerous and difficult to detect. Researchers have therefore started to develop molecular radiation therapy, in which they link radioactive substances to molecules that can attach to the surface of cancer cells. They then inject these targeted radiation sources into the bloodstream.
“Because the molecules circulate around the body, we can target both disseminated and difficult-to-reach metastases,” says Marika Nestor, professor at Uppsala University.
So far, two forms of molecular radiotherapy have been approved by the Swedish Medical Products Agency and are being successfully used against advanced prostate cancer and neuroendocrine tumours. In a flagship project funded by the Sjöberg Foundation, Marika Nestor, together with researchers from Stockholm, Gothenburg, Uppsala, Linköping, Umeå and Lund, will now develop even more variants of this promising form of treatment.
“I have worked with molecular radiotherapy for over twenty years, and the field has huge potential. In our animal models, we have been able to cure tumours with a single dose,” she says.
The first stage in the flagship project is to start a clinical trial of 177Lu-AKIR001, an antibody that is linked to a radioactive isotope of the element lutetium. The antibody binds to a special protein, CD44v6, which is found on the surface of several hard-to-treat cancers: non-small cell lung cancer, an aggressive form of thyroid cancer, the most common form of head and neck cancer, and gynaecological squamous cell carcinoma.
Can provide images of tumours during treatment
One major advantage of using lutetium as an isotope is that it emits two forms of radiation: beta radiation, which kills cancer cells, and gamma radiation, which can be detected by a gamma camera.
“When we have given the first treatment, we can see where in the body the tumours are located and how well they have absorbed the pharmaceutical. We can also see how the radioactivity is distributed in the other body tissues, so we can adjust the next treatment to protect sensitive organs.”
Researchers can also monitor how the tumours respond to treatment, whether they shrink or continue to grow, so it is easier to quickly determine when it is time to change treatment.
“With many other medicines we are working in the dark, but here we can see the process.”
Will search for new targets for molecular radiotherapy
In parallel with the clinical trial, the project team will identify new targets for molecular radiotherapy. They will look for proteins that are found on the surface of cancer cells, but not on the body’s healthy cells. In the next step, they will develop antibodies that bind to these proteins and link them to radioactive lutetium. If the new treatments are successful in animal trials, Nestor believes the journey from the lab bench to the clinic could be much faster than for 177Lu-AKIR001.
“This is a completely new form of medicine, so we have had to work out which kinds of toxicity tests we need to do and how to manufacture and control the pharmaceutical. It has been a long road, but this should be much easier with future pharmaceuticals.”
The researchers hope to enrol the first patient in the 177Lu-AKIR001 clinical trial towards the end of 2024, initially to ensure that the pharmaceutical is safe for patients. Then they will gradually increase the dosage. They will also investigate whether it is better to give the pharmaceutical often and in small amounts, rather than less frequently but in larger doses.
The knowledge gained from this first project will be used in future clinical trials. The researchers hope that 177Lu-AKIR001 will be an approved pharmaceutical within a decade, and that by then more molecular radiotherapies will be ready for clinical trials.
Main applicant:
Marika Nestor, professor, Uppsala University
Co-applicants:
Renske Altena-Kornalijnslijper, docent and acting chief physician, Karolinska University Hospital
Jan Zedenius, professor and chief physician, Karolinska University Hospital
Johanna Svensson, chief physician, Sahlgrenska University Hospital
Peter Bernhardt, professor and lead medical physicist, Sahlgrenska University Hospital
Sara Strandberg, senior lecturer and chief physician, Norrland University Hospital
Helena Lizana, PhD and medical physicist, Norrland University Hospital
Maria Sandström, MD and chief physician, Norrland University Hospital
Johanna Strand, MD and resident physician, Skåne University Hospital Lund
Carl Fredrik Warfvinge, specialty registrar, Skåne University Hospital Lund
Linda Marklund, professor and chief physician, Uppsala University Hospital
Fredrik Frejd, adjunct professor, Uppsala University
Thuy Tran, docent, Karolinska Institutet
Joachim Nilsson, PhD and medical physicist, Karolinska University Hospital
Cecilia Hindorf, docent and medical physicist, Karolinska University Hospital
Anja Lundgren Mortensen, associate senior lecturer, Karolinska Institutet