Therapeutic Efficacy of Alpha-RIT Using a 213Bi-Anti-hCD138 Antibody in a Mouse Model of Ovarian Peritoneal Carcinomatosis

Abstract

PurposeOvarian peritoneal carcinomatosis is a pathology for which effective cures are currently lacking. New research protocols seek to eradicate residual micrometastases following cytoreductive surgery by using hyperthermic intraperitoneal chemotherapy (HIPEC) or radioimmunotherapy (RIT). This study aims to first develop alpha-RIT using an anti-CD138 mAb radiolabeled with an alpha-emitter, bismuth-213 (213Bi-B-B4) and HIPEC in a nude mouse model and second to compare and combine these techniques.Material and methodsA murine model of postoperative ovarian peritoneal carcinomatosis was established. A pilot group of six mice received an intraperitoneal injection of luciferase-tagged SHIN-3 cells and bioluminescence was measured every day. Cytoreductive surgery was performed at day 14 (n = 4) and 29 (n = 2). Because the residual bioluminescence signal measured after surgery was equivalent to that obtained 3 days after the graft, HIPEC or alpha-RIT treatments were applied 3 days after the graft. Ten mice were treated by HIPEC with cisplatine (37.5 mg/mL), 11 with 7.4 MBq of 213Bi-B-B4, seven with 11.1 MBq of 213Bi-B-B4, and 10 mice were treated with the combined therapy (HIPEC + 7.4 MBq of 213Bi-B-B4). Eleven mice received no treatment. Bioluminescence imaging and survival were assessed.ResultsAlpha-RIT 7.4 MBq and 11.1 MBq significantly improved survival (p = 0.0303 and p = 0.0070, respectively), whereas HIPEC and HIPEC + alpha-RIT treatments did not significantly ameliorate survival as compared to the control group.ConclusionSurvival was significantly increased by alpha-RIT treatment in mice with peritoneal carcinomatosis of ovarian origin; however, HIPEC alone or in combination with alpha-RIT had no significant effect.

Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

“…An advantageous property with the 224 Ra-labeled CaCO 3 microparticles was the low amount of radioactivity resulting in significant antitumor effect. A few kilobecquerels of 224 Ra per mouse were sufficient, which are substantially lower than the several hundred kilobecquerels of 213 Bi [13] , [14] , 211 At [15] , [16] , and 212 Pb [18] , [19] , [20] needed in IP α-radioimmunotherapy of mice with IP tumors previously reported. It is difficult to directly compare the therapeutic benefit of the different α-therapies due to variations in cancer models and treatment schedules, although for survival studies a therapeutic index defined as the median survival of the treatment group divided by the median survival of the untreated group can give an indication.…”

“…IP therapy with α-emitters has previously been examined in murine models with two carrier types: nano- to microsized particles [9] , [10] , [11] , [12] and monoclonal antibodies [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] . With particles as carriers for radionuclides, it is possible to choose a size that facilitates a high retention of the particles in the peritoneal cavity [22] , [23] and thus contribute to the therapeutic radiation being delivered in the target location.…”

Ra‐224 labeling of calcium carbonate microparticles for internal α‐therapy: Preparation, stability, and biodistribution in mice

“…When proposing use of an internal α‐emitter for cancer treatment, it is important to choose a radionuclide with physical properties apt for the application. Intraperitoneal therapy with α‐emitters has shown significant potential in murine models previously, mainly with short‐lived nuclides coupled to monoclonal antibodies . With longer lived nuclides, an unfavorable biodistribution in mice without tumors was found after IP injection of 227 Th coupled to trastuzumab .…”

Hypotonic stress enhances colon cancer cell death induced by platinum derivatives and immunologically improves antitumor efficacy of intraperitoneal chemotherapy

“…Animals were euthanized when turning moribund according to predefined criteria, to avoid animal suffering. Peritoneal carcinomatosis index (PCI) was evaluated as previously described . When indicated, 25 mg/kg of the anti‐CD8 antibody (BE0004, Bio X Cell, West Lebanon, NH) or rat IgG2A (BE0089, Bio X Cell) as a control, were injected 3 days before tumor cell injection and every 3 days for 3 weeks.…”