Fractionated Therapy of HER2-Expressing Breast and Ovarian Cancer Xenografts in Mice with Targeted Alpha Emitting 227Th-DOTA-p-benzyl-trastuzumab

Abstract

BackgroundThe aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT) in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate 227Th-DOTA-p-benzyl-trastuzumab.Methodology/Principal FindingsNude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts were treated with 1000 kBq/kg 227Th-trastuzumab as single injection or four injections of 250 kBq/kg with intervals of 4–5 days, 2 weeks, or 4 weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p<0.01) and survival with tumor diameter less than 16 mm was prolonged (p<0.05) in all TAT groups compared to the control groups. No statistically significant differences were seen among the treated groups. In SKBR-3 xenografts tumor growth to 10-fold size was delayed in the single injection and 4–5 days interval groups (p<0.001) and all except the 4 weeks interval TAT group showed improved survival to the control groups (p<0.05). Toxicity was assessed by blood cell counts, clinical chemistry measurements and body weight. Transient reduction in white blood cells was seen for the single injection and 4–5 days interval groups (p<0.05). No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of body weight was significantly prolonged in 4 weeks interval group compared to single injection group (p<0.05) for SKOV-3 animals and in 2 weeks interval group compared with the 4–5 days interval groups (p<0.05) for SKBR-3 animals.Conclusions/SignificanceThe same concentration of radioactivity split into several fractions may improve toxicity of 227Th-radioimmunotherapy while the therapeutic effect is maintained. Thus, it might be possible to increase the cumulative absorbed radiation dose to tumor with acceptable toxicity by fractionation of the dosage.

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

“…25,31,32 Compared with the tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator, which often requires heating, the HOPO chelators are superior due to efficient radiolabeling at ambient temperatures and high stability of formed complexes. 33,34 Mode of Action of TTCs a-Particle emitters exert their effects independently of cell proliferative state and cell cycle phase. Both slow proliferating as well as actively dividing cells can be targeted by TTCs as long as the target antigen is expressed on the cell surface.…”

HER2 Expression Beyond Breast Cancer: Therapeutic Implications for Gynecologic Malignancies

“…Preclinical studies have recently shown the safe applicability of radioimmunotherapy in gynecologic cancer and other tumor types (123, 124). A phase I trial evaluating lead-212 ( 212 Pb)-trastuzumab in patients with HER2 positive ovarian, pancreatic, colon, gastric, endometrial or breast cancer patients documented to have peritoneal studding or positive washings (intraperitoneal disease) is ongoing.…”

Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator–Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms

“…2 Though sound in theory, these designs have been slow to appear in the clinic, with only scarce examples of promising αgenerator immunoconjugates, such as the lintuzumab conjugate 225 Ac-HuM195 8 and the sialic-acid receptor CD33 conjugate 227 Th-CD33-TTC 9 for myeloid leukemia treatment, or 227 Th-DOTA-trastuzumab for treating HER-2 positive breast and ovarian cancer. 10 Reasons for this slow development are largely economical and related to costs associated with radionuclide production, clinical material production, as well as preclinical and clinical studies. Nevertheless, a better understanding of radiometal chelation and biodistribution is also direly needed to advance this field and to provide new chelating platforms that may be tailored on the basis of indication and isotope selection.…”