Intraperitoneal pretargeted radioimmunotherapy for colorectal peritoneal carcinomatosis.
Academic Article
Overview
abstract
Peritoneal carcinomatosis (PC) is considered incurable, and more effective therapies are needed. Herein we test the hypothesis that GPA33-directed intracompartmental pretargeted radioimmunotherapy (PRIT) can cure colorectal PC. Nude mice were implanted intraperitoneally (i.p.) with luciferase-transduced GPA33-expressing SW1222 cells for aggressive PC (e.g., resected tumor mass 0.369 {plus minus} 0.246 g; n = 17 on day (d) 29). For GPA33-PRIT, we administered i.p. a high-affinity anti-GPA33/anti-DOTA bispecific antibody (BsAb), followed by clearing agent (i.v.), and lutetium-177 (Lu-177) or yttrium-86 (Y-86) radiolabeled DOTA-radiohapten (i.p.) 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- vs. three-cycle therapy were evaluated in mice 26-27 d post-tumor implantation. Single-cycle treatment ([177Lu]LuDOTA-Bn 111 MBq; tumor dose: 4992 cGy) significantly prolonged median survival (MS) approximately two-fold to 84.5 d in comparison with controls (P = 0.007). With three-cycle therapy (once weekly, total 333 MBq; tumor dose: 14975 cGy), 6/8 (75%) survived long-term (MS > 183 d). Furthermore, for these treated long-term survivors, one mouse was completely disease-free (microscopic "cure") at necropsy; the others showed stabilized disease, which was detectable during PET-CT using [86Y]DOTA-Bn. Treatment controls had MS ranging from 42-52.5 d (P < 0.001) and 19/20 mice succumbed to progressive i.p. disease by 69 d. 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 TIs of 12 for blood and 12 for kidneys. MTD was not reached.
