Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with211At-MX35-F(ab')2: Influence of Absorbed Tumor Dose and Effect on Long-Term Survival.
The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment.Methods:Mice bearing subcutaneous tumors (50 mm3, NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with211At-MX35-F(ab')2at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit.Results:Effects on tumor growth after fractionated α-radioimmunotherapy with211At-MX35-F(ab')2was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration.Conclusion:Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.
Department of Radiation Physics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden tom.back@radfys.gu.se.
Tom
T
Bäck
LUNAM Université, Oniris, AMaROC, Nantes, France.
Nicolas
N
Chouin
Department of Radiation Physics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Sture
S
Lindegren
Department of Oncology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and.
Helena
H
Kahu
PET and Cyclotron Unit, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
Holger
H
Jensen
Department of Oncology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and.
Per
P
Albertsson
Department of Radiation Physics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Stig
S
Palm
D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001246:Astatine / Q000627:therapeutic use*; D001835:Body Weight / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011829:Radiation Dosage; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D001246:Astatine
211At; alpha-particles; dosimetry; radioimmunotherapy; targeted alpha therapy