Effective cancer therapy by the α-particle emitter [At-211]-astatine in a mouse model of genetically modified NIS-expressing tumors

The sodium/iodide symporter (NIS) gene offers potential for therapy of non-thyroid cancer by gene transfer together with radioiodide (I-131) therapy. However, data from cancer models with NIS but lacking iodide organification indicated that I-131 uptake counterbalanced by rapid efflux may result in low radiation doses insufficient for β-particle-mediated cell kill. Recently, we showed that the α-particle-emitting halogen, At-211 astatide, is transported by NIS, analogous to iodide. α-particles are extreme cytotoxic and selective agents due to their high-LET and short particle path length of a few cell diameters. Here, we treated nude mice (n=25) with advanced solid tumors (volumes 0.2–1ml) established by xenografting the stable NIS-transfected human dedifferentiated thyroid carcinoma cell line, K1-NIS, by fractionated At-211 therapy (i.p.; 1, 0.5 and 1MBq on day 0, 5 and 16). Within 3 months tumors were completely eradicated in all cases. In parallel, mice gained weight and recovered from morbid conditions. During 1 year follow-up no tumor recurrence was measured. In contrast to control groups (max. survival 40d), survival of the NIS-expressing/At-211-treated group was 96% after 6 months and 60% after 1y. Scintigraphy during follow-up showed no tumor-related uptake but decrease of thyroid function in K1-NIS/At-211 mice (no protective protocols). Histopathology of treated mice (23/25) revealed thyroid atrophy. Other affected organs included liver, spleen, lung, stomach/bowel and skin. One mouse had AML, one an ovarian granulosa cell tumor. 2/23 mice had microscopic tumor residues, one a local intramuscular residual tumor. Our results underscore the potential of At-211 for NIS-mediated cytoreductive therapy due to its excellent tumoricidal effect and significant improvement of survival rates. We conclude that At-211 is a candidate for future cancer gene therapy strategies using human NIS or for treatment of non-thyroid tumors such as a subset of mamma carcinomas with endogenous NIS expression.