Radiopharmaceutical therapy (RPT) is now widely recognized as an effective modality transforming cancer management. Within the last decade, prospective clinical trials using 177Lu-labeled therapies have led to the widespread adoption of [177Lu]Lu-DOTA-octreotate therapy for patients with neuroendocrine neoplasia (NEN) (1) and [177Lu]Lu-PSMA RPT for treatment of metastatic castration-resistant prostate cancer (2–5). Interest in theranostics is rising, resulting in significant ongoing RPT research and expanding to other cancer types. In addition to developing different targeting molecules and finding new targets, the use of an alternative therapeutic radiation emitter is an important approach to further optimize RPT efficacy and outcomes for patients. 161Tb is an attractive option for RPT and is gaining global interest.
POTENTIAL ADVANTAGES OF 161TB VERSUS 177LU
Although [177Lu]Lu-DOTA-octreotate and [177Lu]Lu-PSMA RPT are effective therapies for patients with NEN and metastatic castration-resistant prostate cancer, respectively, disease often recurs or progresses for many patients. A likely factor for this limited response is the presence of heterogeneous disease and micrometastatic deposits. Single tumor cells and micrometastases are unlikely to receive lethal radiation from 177Lu because of its mean path length of about 0.7 mm (range, 0.04–1.8 mm), and small deposits receiving suboptimal radiation will eventually progress. In comparison to 177Lu (a β-emitter),161Tb emits similar β-radiation, but with additional conversion electrons and Auger electrons. Both conversion and Auger electrons have a higher linear energy transfer than β-electrons, resulting in a higher concentration of radiation deposited over a short path and greater cell death (6). These favorable physical properties of 161Tb, in comparison to 177Lu, result in higher radiation delivered to single tumor cells and micrometastases (6), which cannot be visualized on PET images. This indicates potential superiority over the currently used 177Lu, increasing radiation delivered to heterogeneous cancer cell components and likely improving clinical outcome.
PRECLINICAL STUDIES
Using a Monte Carlo track-structure code, absorbed radiation doses were computed for both radionuclides. The absorbed dose for the single-cell nucleus was significantly higher for 161Tb than for 177Lu (6). The absorbed dose for 161Tb was in the range of 2.6–3.6 for single-cell models and 2.1–3.0 higher for the cluster formation. Results suggest 161Tb to be superior for irradiating single tumor cells and micrometastases. Other studies have also supported theoretic dose calculations in favor of 161Tb (7–9).
In vitro and in vivo studies have shown the superiority of 161Tb (10–12). An in vitro study for NEN showed that [161Tb]Tb-DOTATOC was 4- to 5-fold more effective in inhibiting tumor viability than were the 177Lu-labeled counterparts and was even more potent with [161Tb]Tb-DOTA-LM3 (a somatostatin receptor antagonist) (13). This result was also confirmed in vivo. Prostate cancer models showed an additive effect of [161Tb]Tb-PSMA-617 compared with [177Lu]Lu-PSMA-617 (10). In vitro experiments demonstrated reduced viability and survival of tumor cells from [161Tb]Tb-PSMA-617. The in vivo experiments demonstrated a dose-dependent effect for tumor growth delay and mouse survival without adverse events. The pharmacokinetics and biodistribution profiles were similar for both RPTs.
Long-term renal damage in nude mice was assessed comparing [161Tb]Tb-folate and [177Lu]Lu-folate (14). The contribution of Auger and conversion electrons from [161Tb]Tb-folate resulted in a 24% higher mean absorbed renal dose (3.0 vs. 2.3 Gy/MBq for [177Lu]Lu-folate). The study suggested that nephropathy was dose-dependent, and additional Auger and conversion electrons at similar activities did not worsen renal damage in this model.
CLINICAL EXPERIENCE AND CURRENT PROSPECTIVE TRIALS
A first-in-humans application of [161Tb]Tb-DOTATOC was administered to 2 patients with NEN (15). The study reported a physiologic distribution similar to that of [177Lu]Lu-peptide receptor radionuclide therapy; uptake by metastases was observed on early and delayed images and without related adverse events, warranting further prospective studies.
Our group is conducting a phase I/II single-center trial on 30 patients with progressive metastatic castration-resistant prostate cancer (VIOLET trial, NCT05521412). It has a dose-escalation design, with 3 cohorts of 3 patients receiving 4.4, 5.5, and 7.4 GBq, followed by a dose expansion phase. Absorbed radiation doses to normal tissues from the first 9 patients demonstrated the expected range for physiologic uptake (16).
A case report demonstrated a 53% PSA decline after administration of 6.5 GBq of [161Tb]Tb-PSMA-617 to a patient whose disease had progressed after 8 cycles of [177Lu]Lu-PSMA-617 (17). The REALITY study (NCT04833517) is capturing single-center experience with [161Tb]Tb-PSMA. In 6 patients with an inadequate response to [177Lu]Lu-PSMA-617, [161Tb]Tb-PSMA-617 delivered markedly higher mean tumor absorbed doses (18). A phase I study is in progress evaluating [161Tb]Tb-DOTA-LM3 (β-plus) for patients with grade 1 and 2 NEN (NCT05359146). Importantly, SPECT/CT (19) and quantitative SPECT/CT (20) of [161Tb]Tb-PSMA is feasible over a range of activities, enabling dosimetry while also producing suitable imaging for clinical review.
SAFETY AND EXPECTED ADVERSE EVENTS OF 161TB-RPT
The radiobiologic effects of 161Tb versus 177Lu can be predicted on the basis of the chemical emission properties. 161Tb and 177Lu share a similar half-life and β-energy (6). Importantly, the additional conversion and Auger emissions from 161Tb is not expected to cause extra significant adverse events because of the subcellular range (2–500 nm) of its path length. The toxicity profile for 161Tb-RPTs ([161Tb]Tb-DOTA-octreotate or [161Tb]Tb-PSMA) is expected to mirror the 177Lu-RPT counterparts, since the biodistribution at off-target somatostatin receptor or prostate-specific membrane antigen–expressing tissues is anticipated to be similar. It is unlikely that significant off-target toxicities will occur because of the addition of conversion and Auger electrons, but prospective studies are needed to assess short- and longer-term adverse effects.
Like 177Lu, 161Tb also emits low-energy γ-rays resulting in radiation exposure to personnel handling the radiopharmaceutical or in contact with the patient after 161Tb-RPT. The risk of exposure will be mitigated using ionizing radiation precautions similar to 177Lu-RPT, such as shielding and dosimetry monitoring. The γ-spectrum peaks at 43.1 and 74.6 keV are more favorable than the 177Lu peaks at 112.9 and 208.5 keV and may result in a shorter stay requirement or even an outpatient procedure, depending on local radiation protection precautions.
The dose delivered per unit of activity differs, with theoretic dosimetry modeling demonstrating that 7.4 GBq of 177Lu is radio equivalent to 5.4 GBq of 161Tb (21). However, biologic kinetics and rates of radiolysis may vary, and direct measurement is also required.
PRODUCTION AND SCALABILITY OF 161TB
161Tb is most commonly produced through neutron irradiation of enriched 160Gd in a nuclear reactor, according to the scheme 160Gd (n,γ) 161Gd → 161Tb (22). The Paul Scherrer Institute has led the production of 161Tb and preclinical studies. More recently, Isotopia Molecular Imaging and TerThera have spearheaded commercial supply. More than 35 research reactors currently in operation have potential capability for 161Tb production, including the Open-Pool Australian Lightwater reactor operated by the Australian Nuclear Science and Technology Organisation. 160Gd is a rare earth obtained primarily from bastnasite; supply is dominated from calutrons in Russia (an electromagnetic separation process), which may be a rate-limiting step. There is, however, a similar issue with many target materials required for radiometal production (23).
Cyclotron production of 161Tb has also been proposed by irradiating natural dysprosium with γ-rays obtained by decelerating an electron beam, with an energy of 55 MeV demonstrated experimentally (24).
FUTURE PERSPECTIVES
Cancer heterogeneity, including the presence of micrometastatic disease, is one of the important factors associated with variable oncologic responses from 177Lu-RPT. 161Tb possesses favorable radiation properties compared with 177Lu. 161Tb-RPT is expected to be well tolerated, analogous to 177Lu-RPT, but with higher effectiveness through additional conversion and Auger emissions, likely leading to improved effectiveness and patient outcomes. Ongoing and upcoming prospective trials will enable careful clinical evaluation and assessment for adverse effects. It is important to expand effective RPT options for targetable cancers to meet clinical needs, but strong prospective data, scalability with reliable production, and affordability are fundamental considerations.
DISCLOSURE
Isotopia supplies [161Tb]Tb and PSMA-I&T cold kit for the VIOLET trial as part of a commercialization agreement with the Peter MacCallum Cancer Centre. No other potential conflict of interest relevant to this article was reported.
Footnotes
Published online Apr. 11, 2024.
- © 2024 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication February 13, 2024.
- Revision received March 15, 2024.