A groundbreaking radioimmunotherapy approach utilizing Terbium-161 (¹⁶¹Tb) has demonstrated remarkable success in eliminating ovarian cancer stem cells (CSCs) in preclinical models, significantly outperforming the current gold standard Lutetium-177 (¹⁷⁷Lu). The research, published in the July 2025 issue of The Journal of Nuclear Medicine, represents a major advancement in targeting the most resilient and dangerous cancer cell populations that drive tumor relapse and treatment resistance.
Revolutionary Approach to Cancer Stem Cell Elimination
Cancer stem cells pose one of the greatest challenges in oncology due to their capacity for self-renewal, tumorigenesis, and resistance to conventional therapies. These highly tumorigenic cells play a key role in tumor relapse, metastasis, and therapy resistance, making their elimination crucial for achieving durable cancer remissions.
"Our study sought to investigate the effectiveness of a new radionuclide Terbium-161 (¹⁶¹Tb) for eradicating CSCs due to emission of short-ranged conversion and Auger electrons-besides beta-minus particle-successfully eliminated ovarian CSCs in contrast to Lutetium-177 (¹⁷⁷Lu)," explained Dr. Jürgen Grünberg, PhD, senior scientist at the Center for Radiopharmaceutical Sciences at the Paul Scherrer Institute in Villigen, Switzerland.
Superior Therapeutic Performance
The study demonstrated that ¹⁶¹Tb-based radioimmunotherapy achieved complete elimination of all detected ovarian cancer stem cells and their differentiated progeny in live animal models. This milestone outcome effectively prevented tumor growth, a result rarely achieved in preclinical oncology models.
Researchers first confirmed the presence of L1CAM+/CD133+ ovarian cancer stem cells within patient-derived tumor samples, establishing a vital clinical foundation for targeted intervention. The subsequent preparation of radioimmunoconjugates involved linking either ¹⁶¹Tb or ¹⁷⁷Lu to the chimeric antibody chCE7 via a DOTA chelator, ensuring stable in vivo delivery and selective binding to the L1CAM antigen expressed on ovarian CSCs.
Mechanistic Advantages of Terbium-161
The superior efficacy of ¹⁶¹Tb stems from its unique emission profile. Unlike ¹⁷⁷Lu, Terbium-161 emits short-range conversion and Auger electrons alongside beta particles, conferring an intensified cytotoxic payload that amplifies DNA damage within CSCs upon molecular binding.
Dr. Grünberg highlighted that "¹⁶¹Tb's emission of short-ranged electrons results in highly localized energy deposition. This radiobiological advantage facilitates the infliction of irreparable double-stranded DNA breaks within CSCs, overcoming their notorious radioresistance."
This enhanced particle profile enables more efficient irradiation of target cells, capitalizing on the spatial precision inherent to radioimmunotherapy while maximizing tumor cell kill and sparing normal cells.
Targeting Protected Cancer Reservoirs
The investigation revealed the pivotal role of tubular and sheathing structures within ovarian tumors that facilitate CSC protection and survival. The potent emission characteristics of ¹⁶¹Tb enabled the radioimmunotherapy to effectively penetrate these microenvironments, demonstrating capacity to disrupt even the most sheltered cancer reservoirs.
This capability may be transformative in preventing tumor recurrence, addressing a significant clinical obstacle in current ovarian cancer management where traditional treatment strategies often fail to effectively target these resilient subpopulations.
Safety Profile and Clinical Translation Potential
The study incorporated rigorous control experiments to ensure selective targeting and rule out systemic toxicity. Histological analysis and monitoring of organ function in treated animals confirmed favorable safety profiles for ¹⁶¹Tb radioimmunotherapy, a critical requirement for clinical translation.
Dr. Tihomir Todorov emphasized the translational potential of this work, advocating for further development of ¹⁶¹Tb-based therapeutics as tailored interventions within the personalized medicine framework. With the integration of molecular imaging and theranostic capabilities, such radionuclide therapies could simultaneously offer diagnostic clarity and therapeutic precision.
Broader Implications for Cancer Treatment
The success of ¹⁶¹Tb-based radioimmunotherapy underscores the evolving paradigm of harnessing radioisotope physics for precision medicine. The emission properties of radionuclides can be strategically leveraged to not only destroy primary tumor cells but also target elusive cellular subsets like CSCs, which evade standard chemotherapeutic and radiotherapeutic tactics.
This dual utility holds promise not only for managing ovarian cancer but also for expanding the treatment landscape for other malignancies driven by resistant CSC populations. The research provides compelling proof of concept that augments the arsenal against ovarian cancer's deadliest element—the cancer stem cell—and charts a promising course toward clinically viable radioimmunotherapies capable of overcoming intrinsic treatment resistance.
