Preclinical evaluation of 212Pb-based alpha-particle therapy for neuroendocrine tumors: dosimetry and potential toxicities

Dongyoul Lee; Stephen Graves; Dijie Liu; Hsiang Wen; Diana Zepeda-Orozco; Mark Madsen; Susan Walsh; G Watkins; Yusuf Menda; Michael Schultz; David Bushnell

Objectives: Peptide receptor-targeted radionuclide therapy (PRRT) targeting somatostatin receptor subtype 2 (SSTR2) has emerged as a promising therapy for neuroendocrine tumors. Beta-particle PRRT using 177Lu-DOTA-tyr3-octreotate (177Lu-DOTATATE) has been shown to significantly improve progression-free survival for NET patients compared to the standard of care treatment in a Phase 3 trial (1). However, the overall response rate is limited and complete responses are rare. Emerging evidence suggests that alpha-particle PRRT (α-PRRT) has the potential to improve tumor response. However, concerns regarding potential toxicities to normal organs and tissues (e.g., kidneys, bone marrow) mandate development and evaluation of personalized dosimetric approaches which can be used in clinical studies to reduce these toxicities. In this study, we evaluated potential renal and bone marrow toxicities arising from 212Pb-DOTA-tyr3-octreotide (212Pb-DOTATOC) in an animal model. A dosimetry study was performed on each animal with the aim of examining the relationship between localized 212Pb α+β dose to kidneys (a dose-limiting organ for beta PRRT) and markers of kidney function, injury, and kidney morphological changes. Methods: 14.8 MBq of 203Pb-DOTATOC was administered to tumor-free CD1-Elite (SOPF) mice via tail vein and SPECT/CT images were obtained at 1.5 h and 22 h post-injection. After 1.5 weeks, the same group of mice (8 mice) was divided into 4 groups, and each group was injected with escalating activities of 212Pb-DOTATOC (0.037, 0.074, 0.118, and 0.178 MBq/g). The absorbed dose (alpha/beta) from 212Pb-DOTATOC was estimated by the OLINDA/EXM software based on the time-activity curves obtained from 203Pb-DOTATOC SPECT/CT images. The renal mass of each mouse used in this calculation was obtained from the CT-delineated volume with an assumed density of 1.05 g/cm3. In order to assess acute and chronic kidney injury by the radiotherapeutic, blood or urine were collected at day 1, day 3, week 3, week 12, and 7 months post-injection for analysis of nephrotoxicity parameters NGal (Neutrophil gelatinase-associated lipocalin) and Cystatin C. Another group of four mice was injected with the highest dose (0.178 MBq/g), and hematological toxicity was evaluated by serial complete blood counts (up to 5 weeks). Results: Escalated activities of 212Pb-DOTATOC resulted in increased estimated alpha doses in kidneys (6.6 Gy to 35.2 Gy). Contributions of beta particles were minimal compared to the alpha particles accounting for less than 4% of the total absorbed dose. We found evidence for mild acute renal tubular toxicity based on measures of serum NGAL levels in 6 of the 8 treated mice, although the elevated levels appeared to show no relationship to the kidney doses in this study. There was no evidence of changes in renal function in this group when evaluated by continued normal levels of serum Cystatin C out to 12 weeks post administration of 212Pb-DOTATOC. We observed a 50% average decline in platelets and 40% average decline in WBC 2-3 weeks following administration of 0.178 MBq/g of 212Pb-DOTATOC in mice. These nadir values returned to baseline levels at 5 weeks post administration. Ongoing kidney histopathology studies will provide further information concerning the level of chronic renal toxicity of 212Pb-DOTATOC using this dosing strategy. Conclusions: 203Pb imaging-based dosimetry can be utilized for 212Pb dose estimation and can inform personalized dosimetry-guided therapy with 212Pb-based therapeutics. Administration of 212Pb-DOTATOC (0.037 - 0.178 MBq/g) resulted in mild acute tubular toxicity and reversible hematological toxicity. NGal is a sensitive biomarker for acute renal tubular toxicity, but observed levels were not proportional to increased absorbed alpha doses in this study.

Preclinical evaluation of 212Pb-based alpha-particle therapy for neuroendocrine tumors: dosimetry and potential toxicities

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