Summary: Combination alpha- and beta-radionuclide therapy shows promise and tolerability for colorectal cancer, effectively targeting tumor cells and reducing side effects, while addressing challenges such as treatment resistance and tumor heterogeneity.

Key Takeaways:

  1. Combination alpha- and beta-radionuclide therapy is effective and well-tolerated for colorectal cancer, reducing side effects while targeting tumor cells.
  2. This dual radionuclide approach can address challenges like treatment resistance and tumor heterogeneity by using radionuclides with different radiobiological properties.
  3. Preclinical studies show that combined 177Lu/225Ac therapy is as effective as mono-therapy in shrinking tumors and is well-tolerated, offering a versatile treatment option for a larger patient population.


Combination alpha- and beta-radionuclide therapy is promising and well-tolerated for colorectal cancer. Research presented at the 2024 Society of Nuclear Medicine and Molecular Imaging meeting shows this approach effectively targets tumor cells, reducing side effects.

Challenges in Radionuclide Therapy

Despite the successes of targeted radionuclide therapy, challenges remain; some patients do not respond to the chosen radionuclide therapy, while others experience relapse or develop treatment resistance. Tumor heterogeneity presents another obstacle for targeted radionuclide therapy as differences in tumor make-up can impact effectiveness.

“Combining radionuclides with different radiobiological properties and administering them simultaneously may help overcome some of these issues,” says Sara S. Rinne, postdoctoral associate in radiology at Weill Cornell Medicine in New York, New York. “The use of both alpha- and beta-emitting nuclides could better address tumor heterogeneity due to their varied penetration depths and ability to induce different radiobiological effects, thus creating more complex damage to the tumor and offering a potentially successful treatment approach for a larger patient population.”

Promise in Preclinical Models

The study aimed to evaluate the feasibility and therapeutic efficacy of simultaneously administered 177Lu/225Ac pretargeted radioimmunotherapy and compare it to separate 177Lu and 225Ac therapies on human colorectal cancer xenografts in mice. Biodistribution and autoradiography experiments were conducted to determine feasibility and dosage. Mice with colorectal cancer xenografts were then treated with mono- or combination therapy and monitored over several months. 

Biodistribution and autoradiography experiments confirmed that the combination therapy could bind to colorectal cancer xenografts. Combined 177Lu/225Ac pretargeted radioimmunotherapy was equally as potent as mono-therapy in inducing tumor shrinkage and cures and was well-tolerated in the preclinical model.

New Hope for Cancer Treatment

“The ability to simultaneously deliver different radioisotopes with complementary radiobiological properties creates new opportunities for improving therapy outcomes and improving patient care,” notes Rinne.

“Furthermore, our study’s results highlight the great promise and versatility of pretargeted radioimmunotherapy to treat with curative intent. Overall, pre-targeted dual-isotope therapy has the potential to be a versatile approach to help a larger patient population and overcome existing barriers to successful targeted radionuclide therapy,” she adds.

Featured image:  Autoradiography images of GPA33(+) SW1222 xenograft sections acquired using an ionizing-radiation quantum imaging detector (iQID) camera. The images effectively illustrate that the DOTA-PRIT (DOTA pretargeted radioimmunotherapy) approach can be used to simultaneously deliver 225Ac and 177Lu to tumors. Mice were injected with 177Lu- or 225Ac-radioligand alone (first and second row, respectively), or a 177Lu/225Ac mixture (row 3 and 4), after pretargeting with anti-GPA33/anti-DOTA bispecific antibody. First column shows the combined signal (177Lu and 225Ac together), second column (⍺-counts) shows uptake of 225Ac, and third column (β-counts) show 177Lu-uptake. Fourth column shows an overlay of the 225Ac-signal (red) and 177Lu-signal (green).