Is ¹⁶¹Tb Really Happening?

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.