Brief Intraperitoneal Radioimmunotherapy of Small Peritoneal Carcinomatosis Using High Activities of Noninternalizing ¹²⁵I-Labeled Monoclonal Antibodies

Abstract

We assessed the efficiency and toxicity of brief intraperitoneal radioimmunotherapy using high activities of 125 I-labeled monoclonal antibody (mAb) in the treatment of small-volume peritoneal carcinomatosis. Methods: Brief intraperitoneal radioimmunotherapy consisted of a 185-MBq (740 MBq/mg) intraperitoneal injection of 125 I-35A7 (an anti-carcinoembryonic antigen mAb) into athymic nude mice 4 d after peritoneal tumor xenografting and, after 1 h, abundant washing of the peritoneal cavity with saline solution to remove unbound radioactivity. Another group of mice received this treatment plus a 37-MBq intravenous injection of 125 I-35A7 on day 7 or 11 after grafting. Control groups received a brief treatment followed by an additional intravenous injection on day 7 of either saline solution or irrelevant 125 I-PX. Tumor growth was monitored by bioluminescence imaging and SPECT/CT, and hematologic toxicity was evaluated by complete blood counts. Survival time was reported, and the mice were sacrificed when the bioluminescence signal reached 4.5 · 10 7 photons/s. The biodistribution of 125 I-35A7 mAb after intravenous or brief treatment was assessed, and the mean absorbed irradiation dose by organs and tumors was calculated using the MIRD formalism. Results: Mild, transient hematologic toxicity was observed after the brief treatment plus intravenous 125 I-mAb, with no weight loss. Median survival increased from 32 d in the control groups, to 46 d in the brief treatment group, to 66 d in the group additionally receiving intravenous treatment on day 11, to 73 d in the group additionally receiving intravenous treatment on day 7. The brief treatment alone resulted in a 3-fold higher tumor-toblood uptake ratio than did the standard intravenous treatment, and the mean absorbed irradiation doses by tumors were 11.6 Gy for the brief treatment and 16.7 Gy for the additional intravenous treatment. For healthy tissues other than blood, the mean absorbed irradiation dose did not exceed 1 Gy after brief treatment and 4.2 Gy after intravenous treatment. Conclusion: The efficiency, low toxicity, and high tumor-to-healthy tissue uptake ratio associated with brief intraperitoneal 125 I-35A7 radioimmunotherapy suggest that this method can be used in combination with radiation-synergistic drugs in the therapy of smallvolume peritoneal carcinomatosis after cytoreductive surgery.

Molecular and cellular effects of Auger emitters: 2008–2011

“…Two additional studies were recently published by members of Pouget ' s group (Santoro et al 2009, Boudousq et al 2010) that build upon the earlier studies discussed above. Santoro et al (2009) came to the conclusion that RIT using the Auger emitter, 125 I, should only be considered for treatment of small tumors, reporting some effi cacy in the treatment of small-volume peritoneal carcinomatosis.…”

“…Although this approach was primarily presented as an imaging approach (Cornelissen et al 2011a), the authors speculate on possible therapeutic roles for targeting DNA double-strand breaks with their Auger emitter labeled anti-γ H2AX compound. layers has been reported (Boudousq et al 2010). 125 I-antiCEA has been found to be eff ective with low toxicity in the therapy of small volume peritoneal carcinomatosis after cytoreductive surgery and is a viable alternative to α and β emitters.…”

Intraperitoneal photodynamic therapy mediated by a fullerene in a mouse model of abdominal dissemination of colon adenocarcinoma

“…This is especially important in cases such as disseminated intraperitoneal tumor where it is impossible to measure tumor dimensions (38,39). Bioluminescence imaging of disseminated peritoneal tumor has been used to study response to therapies such as radioimmunotherapy with I 125 -labeled antibodies (40) and conjugates between daidzein and alliinase (41).…”

Emerging Trends for Radioimmunotherapy in Solid Tumors

“…Recently, a ''brief intraperitoneal RIT'' approach involving high dose administration of noninternalizing 125 I-35A7 was described. 19 In contrast to the previous study where 37 MBq 125 I-labeled MAbs were administered intravenously, in ''brief intraperitoneal RIT'' 185 MBq of radioimmunoconjugate was administered intraperitoneally and the unbound antibody was removed 1 hour postadministration by flushing the peritoneal cavity with saline. SPECT imaging indicated that after flushing the radioiodine signal was associated only with the intraperitoneal tumors.…”

“…Several studies have been undertaken to identify the most suitable radionuclides (b-, a-or auger-emitters), antibody formats [F(ab¢) 2 IgG, IgM] and types (internalizing vs. noninternalizing), and evaluating the toxicity of radionuclides on the peritoneal membrane. [18][19][20][21][22][23][24] In the context of intraperitoneal RIT involving a-particle emitters, recent studies have also explored their utility in several ways: multiple administrations 25 and the impact of using variable specific activities 26 ; compared the efficacy of intraperitoneal RIT with pretargeted intraperitoneal RIT 27 ; and investigated the impact of antibody glycosylation on efficacy. 28 …”