Model of Intraperitoneal Targeted α-Particle Therapy Shows That Posttherapy Cold-Antibody Boost Enhances Microtumor Radiation Dose and Treatable Tumor Sizes.

Intraperitoneally administered radiolabeled monoclonal antibodies (mAbs) have been tested in several clinical trials, often with promising results, but have never proven curative. Methods: We have previously presented simulations of clinically relevant amounts of intraperitoneal 90Y-mAbs for treatment of minimal disease and shown that such treatments are unlikely to eradicate microtumors. Our previous model simulated the kinetics of intraperitoneally infused radiolabeled mAbs in humans and showed the benefit of instead using α-emitters such as 211At. In the current work, we introduce penetration of mAbs into microtumors with radii of up to 400 μm. Calculations were performed using dynamic simulation software. To determine the radiation dose distribution in nonvascularized microtumors of various sizes after intraperitoneal 211At-radioimmunotherapy, we used an in-house-developed Monte Carlo program for microdosimetry. Our aim was to find methods that optimize the therapy for as wide a tumor size range as possible. Results: Our results show that high-specific-activity radiolabeled mAbs that are bound to a tumor surface will penetrate slowly compared with the half-lives of 211At and shorter-lived radionuclides. The inner-core cells of tumors with radii exceeding 100 μm may therefore not be sufficiently irradiated. For lower specific activities, the penetration rate and dose distribution will be more favorable for such tumors, but the dose to smaller microtumors and single cells will be low. Conclusion: Our calculations show that the addition of a boost with unlabeled mAb 1-5 h after therapy results in sufficient absorbed doses both to single cells and throughout microtumors up to approximately 300 μm in radius. This finding should also hold for other high-affinity mAbs and short-lived α-emitters.