Cure of human ovarian carcinoma solid xenografts by fractionated [211At] alpha-radioimmunotherapy: Influence of tumor absorbed dose and effect on long-term survival

The goal of this study was to investigate if targeted alpha therapy (TAT) could be used to successfully treat also macro tumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous (i.v.) fractionated regimen of alpha-radioimmunotherapy (α-RIT) in a subcutaneous (s.c.) tumor model in mice. We aimed at evaluating the absorbed dose levels required for tumor eradication and to monitor tumor growth, as well as the long-term survival after treatment.

METHODS: Mice bearing s.c.-tumors (50 mm3, NIH:OVCAR-3) were i.v.-injected repeatedly (1 to 3 injections, 7-10 days apart allowing bone-marrow recovery) with (211)At-MX35-F(ab')2 at different activities (close to acute myelotoxicity). Mean absorbed dose to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 days and survival for 1 year after treatment. Toxicity analysis included body weight, WBC and hematocrit.

RESULTS: Effects on tumor growth following fractionated α-RIT with (211)At-MX35-F(ab')2 was strong and dose-dependent. Complete remission (TFF=100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high and long-term toxicity effects (up to 60 weeks) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 weeks. Toxicity was also seen by reduced body weight. WBC-analysis after α-RIT indicated bone marrow recovery for the low activity groups, while for high activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 weeks after therapy). The main external indication of poor health was dehydration.

CONCLUSION: Having observed complete eradication of solid tumor xenografts, we conclude that TAT regimens could stretch beyond the realm of micrometastatic disease and be eradicative also for macro tumors. Our observations indicated that at least 10 Gy is required. This was in good agreement with the calculated TCP. Considering a RBE of 5, this dose level seemed reasonable. However, complete remission was achieved first at activity levels close-to lethal and was accompanied with biological effects that reduced the long-term survival.