Comparative studies on the therapeutic benefit of targeted α-particle radiation therapy for the treatment of disseminated intraperitoneal disease

Abstract

Identification of the appropriate combination of radionuclide, target and targeting vehicle is critical for successful radioimmunotherapy. For the treatment of disseminated peritoneal diseases such as pancreatic or ovarian cancer, α-emitting radionuclides have been proposed for targeted radiation therapy. This laboratory has taken a systematic approach investigating targeted α-radiation therapy, allowing comparisons to now be made between ²¹¹At, ²²⁷Th, ²¹³Bi and ²¹²Pb. Herein, trastuzumab radiolabeled with ²¹¹At and ²²⁷Th was evaluated for therapeutic efficacy in the LS-174T i.p. tumor model. A dose escalation study was conducted with each radioimmunoconjugate (RIC). Therapeutic benefit was realized with ²¹¹At-trastuzumab with doses of 20, 30 and 40 μCi. At doses >40 μCi, toxicity was observed with greater weight loss and 2-fold higher decrease in the platelet counts. Following a second study comparing the effect of 20, 30 and 40 μCi of ²¹¹At-trastuzumab, 30 μCi was selected as the dose for future studies. A parallel study was performed evaluating 0.25, 0.5, 1.0, 2.0 and 5.0 μCi of ²²⁷Th-trastuzumab. The 0.5 and 1.0 μCi injected dose resulted in a therapeutic response; a lower degree of weight loss was experienced by the mice in the 0.5 μCi cohort. When the data is normalized for comparing ²¹¹At, ²²⁷Th, ²¹³Bi and ²¹²Pb, the choice of radionuclide for RIT is perhaps not entirely based on simple therapeutic efficacy, other factors may play a role in choosing the “right” radionuclide.