Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis

Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioim-munotherapy (PRIT) can cure colorectal peritoneal carcinoma-tosis. Nude mice were implanted intraperitoneally with lucifer-ase-transduced GPA33-expressing SW1222 cells for aggressive peritoneal carcinomatosis (e.g., resected tumor mass 0.369 + 0.246 g; n = 17 on day 29). For GPA33-PRIT, we administered intraperitoneally a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (intrave-nous), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radio-labeled DOTA-radiohapten (intraperitoneal) for beta/gamma-emitter therapy and PET imaging, respectively. The DOTA-radiohaptens were prepared from S-2-(4-aminobenzyl)-1,4,7, 10-tetraazacyclododecane tetraacetic acid chelate (DOTA-Bn). Efficacy and toxicity of single-versus three-cycle therapy were evaluated in mice 26-27 days post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4,992 cGy) significantly prolonged median survival (MS) approx-imately 2-fold to 84.5 days in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14,975 cGy), 6/8 (75%) survived long-term (MS > 183 days). Furthermore, for these treated long-term survivors, 1 mouse was completely disease free (microscopic cure) at necropsy; the others showed stabilized disease, which was detect-able during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 days (P < 0.001) and 19/20 mice succumbed to progressive intraperitoneal disease by 69 days. Multi-cycle GPA33 DOTA-PRIT significantly prolongs survival with reversible myelosuppression and no chronic marrow (929 cGy to blood) or kidney (982 cGy) radiotoxicity, with therapeutic indices of 12 for blood and 12 for kidneys. MTD was not reached.

Automated summary

This study tests a treatment method for peritoneal carcinomatosis that targets GPA33 using intracompartmental pretargeted radioimmunotherapy. The results show that this method effectively prolongs the survival of tumor patients without significant radiotoxicity.