Detection and therapy of neuroblastoma minimal residual disease using [64/67Cu]Cu-SARTATE in a preclinical model of hepatic metastases

Abstract

Background A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [64Cu]Cu-SARTATE to detect and monitor the disease and [67Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [64Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [67Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation. Results PET imaging and ex vivo biodistribution confirmed tumor uptake of [64Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [64Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [67Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [67Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064). Conclusions Clinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [64/67Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD.

An abbreviated therapy-dosimetric equation for the companion diagnostic/therapeutic [64/67Cu]Cu-SARTATE

“…Figure 1 also shows the corresponding SUR-versus-time curve. At t = 9 h post-injection, the SUR value is close to 1 (for the above K i -D and F D values), thus indicating that tumor- and blood-activity concentration are close, of about 27 × 10 3 Bq g −1 (for a mean [ 64 Cu]Cu-SARTATE IA of 3.61 × 10 6 Bq [ 1 ]). An ± 1-h uptake-time variability around peak time results in a + 19/− 17% increase/decrease in SUR, respectively.…”

“…Mean blood-clearance data provided by Dearling et al were used to fit the common IF of [ 64/67 Cu]Cu-SARTATE, after removing decay correction (GraphPad Prism 6 software) [ 1 ]: IF( t ) = Y 0 × exp(− α × t ) with Y 0 = 4.11939 %IA/g (IA: injected activity in Bq) and α = 0.18934 h −1 (n = 4; R = 0.999; P < 0.01; 95%-CI of 4.08542–4.15335 and of 0.18579–0.19289, respectively). As a result, involving [ 67 Cu]Cu-SARTATE was 783 × IA mL −1 (= [ Y 0 × IA × 3600]/[100 × α ]), assuming tissue density of 1 g mL −1 .…”

“…Companion diagnostic/therapeutic radiopharmaceuticals (D-RP/T-RP) are the basis of the theranostic strategy that uses a molecule designed for a specific target, which is labeled with a suitable pair of radionuclides [ 1 , 2 ]. The strategy consists in a first diagnostic PET-imaging scan with D-RP that selects patients who can subsequently benefit from a therapy with T-RP.…”

“…Recently, the [ 64 Cu]Cu-SARTATE biodistribution was assessed by Dearling et al in a preclinical intrahepatic model of neuroblastoma (NB) metastatic disease, representing minimal residual disease (MRD), along with potential therapeutic effect of [ 67 Cu]Cu-SARTATE [ 1 ]. Unlike the companion 64 Cu/ 177 Lu-cetuximab, whose input function (IF, i.e., RP-blood time-activity-curve) was different for diagnosis/therapy (time constant of mono-exponentially decaying IF of 0.0830 h −1 and 0.0224 h −1 , uncorrected for physical decay, respectively), the companion [ 64 / 67 Cu]Cu-SARTATE provides the opportunity of using a “true” theranostic pair of radionuclides, resulting in identical D-RP/T-RP uptake features [ 1 , 2 ].…”

“…The present theoretical commentary aims at deriving an abbreviated equation of therapeutic with [ 67 Cu]Cu-SARTATE, from [ 64 Cu]Cu-SARTATE uptake assessed in a single initial diagnostic scan. In the pre-clinical framework of Dearling et al, this equation was refined by using the common mouse IF of [ 64/67 Cu]Cu-SARTATE and the physical-decay-rate constant of the 64/67 Cu radionuclides [ 1 ].…”