Synapse - Efficacy of HER2-targeted intraperitoneal (225)Ac α-pretargeted radioimmunotherapy for small-volume ovarian peritoneal carcinomatosis

Efficacy of HER2-targeted intraperitoneal (225)Ac α-pretargeted radioimmunotherapy for small-volume ovarian peritoneal carcinomatosis Journal Article

Authors:	Chung, S. K.; Vargas, D. B.; Chandler, C. S.; Katugampola, S.; Veach, D. R.; McDevitt, M. R.; Seo, S. H.; Vaughn, B. A.; Rinne, S. S.; Punzalan, B.; Patel, M.; Xu, H.; Guo, H. F.; Zanzonico, P. B.; Monette, S.; Yang, G.; Ouerfelli, O.; Nash, G. M.; Cercek, A.; Fung, E. K.; Howell, R. W.; Larson, S. M.; Cheal, S. M.; Cheung, N. K. V.
Article Title:	Efficacy of HER2-targeted intraperitoneal (225)Ac α-pretargeted radioimmunotherapy for small-volume ovarian peritoneal carcinomatosis
Abstract:	Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted alpha-therapy with the alpha-particle-emitting radionuclide Ac-225 (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) Ac-225-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0,10(5) SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 Ac-225-PRIT (37 kBq/cycle as Ac-225-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of Ac-225-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative bio-logical effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to a-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 Ac-225-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted alpha-therapy using the anti-HER2 Ac-225-PRIT system is a potential treatment for otherwise incurable EOC.
Keywords:	antibody; therapy; xenografts; peritoneal carcinomatosis; affinity; ac-225; pretargeted radioimmunotherapy
Journal Title:	Journal of Nuclear Medicine
Volume:	64
Issue:	9
ISSN:	0161-5505
Publisher:	Society of Nuclear Medicine
Date Published:	2023-09-01
Start Page:	1439
End Page:	1445
Language:	English
ACCESSION:	WOS:001120138300020
DOI:	10.2967/jnumed.122.265095
PROVIDER:	wos
PMCID:	PMC10478816
PUBMED:	37348919
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Sarah M. Cheal -- Source: Wos