A novel radioimmunotherapy regimen has demonstrated the potential to effectively treat human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as reported in the November 2023 issue of The Journal of Nuclear Medicine. This innovative approach pre-treats tumors prior to administering targeted alpha-radioimmunotherapy, leading to significant and long-lasting responses in a research model, with minimal associated toxicities.
HER2-positive breast cancer represents a particularly aggressive subtype, affecting approximately 15–20% of breast cancer patients. Despite advancements in HER2-targeted therapies, challenges persist, including adverse events and resistance to treatment. Dr. Sarah Cheal, an assistant professor at Weill Cornell Medicine, highlighted the limitations of previous HER2-targeted radioimmunotherapy methods, noting that while they showed effectiveness, they also resulted in high toxicity due to the retention of alpha-particles in the body.
In this latest study, researchers utilized a pretargeted radioimmunotherapy (PRIT) approach designed to directly treat the tumor while minimizing the absorption of harmful alpha-particles in healthy tissues. The regimen involved a three-step intravenous process: the administration of a bispecific anti-HER2/anti-DOTA antibody, followed by a clearing agent, and finally, the delivery of 225 Ac-Pr radioimmunotherapy.
Research Findings and Efficacy
The efficacy of the 225 Ac-Pr dosing during PRIT was first evaluated in the BT-474 breast cancer xenograft model. Following this, the regimen was tested in mice with either the BT-474 xenograft or a patient-derived xenograft. Mice received one or two cycles of 225 Ac-PRIT, spaced one week apart. A dose escalation study was conducted to assess the radiation dose absorbed by the kidneys, an important factor in evaluating potential nephrotoxicity.
In the BT-474 model, the results were striking: 100% of the mice achieved complete responses, and 85% achieved histologic cures. Both one-cycle and two-cycle treatments proved equally effective, with no chronic radiation toxicity observed. In the patient-derived xenograft model, a single treatment with 225 Ac-PRIT resulted in a 60% complete response rate and significantly prolonged survival compared to untreated mice.
Potential for Clinical Application
The research team also successfully identified the dosage threshold at which severe chronic nephrotoxicity occurred, providing crucial data for future applications. Dr. Nai Kong Cheung, a member and attending physician in Pediatric Oncology at Memorial Sloan Kettering Cancer Center, emphasized the study’s implications, stating, “This study illustrates the curative potential of 225 Ac-PRIT as a treatment for highly aggressive subtypes of HER2-positive breast cancer.”
If these promising results can be translated into clinical practice, the HER2-directed 225 Ac therapy may offer new treatment avenues not only for breast cancer but also for other solid tumors that express HER2. This advancement represents a significant step forward in the ongoing battle against aggressive breast cancer subtypes, offering hope to patients facing limited options.
For further details, consult the study: Sara S. Rinne et al, “225 Ac α-Pretargeted Radioimmunotherapy of Human Epidermal Growth Factor Receptor 2–Expressing Breast Cancer,” Journal of Nuclear Medicine (2023). DOI: 10.2967/jnumed.125.269601.
