title: Optimizing radioimmunotherapy by matching dose distribution with tumor structure using 3D reconstructions of serial images.
abstract: The biological effect of radioimmunotherapy (RIT) is most commonly assessed in terms of the absorbed radiation dose. In tumor, conventional dosimetry methods assume a uniform radionuclide and calculate a mean dose throughout the tumor. However, the vasculature of solid tumors tends to be highly irregular and the systemic delivery of antibodies is therefore heterogeneous. Tumor-specific antibodies preferentially localize in the viable, radiosensitive parts of the tumor whereas non-specific antibodies can penetrate into the necrosis where the dose is wasted. As a result, the observed biological effect can be very different to the predicted effect from conventional dose estimates. The purpose of this study is to assess the potential for optimizing the biological effect of RIT by matching the dose-distribution with tumor structure through the selection of appropriate antibodies and radionuclides. Storage phosphor plate technology was used to acquire images of the antibody distribution in serial tumor sections. Images of the distributions of a trivalent (TFM), bivalent (A5B7-IgG), monovalent (MFE-23) and a non-specific antibody (MOPC) were obtained. These images were registered with corresponding images showing tumor morphology. Serial images were reconstructed to form 3D maps of the antibody distribution and tumor structure. Convolution of the image of antibody distribution with beta dose point kernals generated dose-rate distributions for 14C, 131I and 90Y. These were statistically compared with the tumor structure. The highest correlation was obtained for the multivalent antibodies combined with 131I, due to specific retention in viable areas of tumor coupled with the fact that much of the dose was deposted locally. With decreasing avidity the correlation also decreased and with the non-specific antibody this correlation was negative, indicating higher concentrations in the necrotic regions. In conclusion, the dose distribution can be optimized in tumor by selecting the appropriate antibodies and radionuclides. This has the potential to lead to a considerable enhancement of the efficacy of RIT in the clinic.
authors.affiliation: CRC Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. a.flynn@ucl.ac.uk
authors.forename: A A
authors.initials: AA
authors.lastname: Flynn
authors.forename: R B
authors.initials: RB
authors.lastname: Pedley
authors.forename: A J
authors.initials: AJ
authors.lastname: Green
authors.forename: G M
authors.initials: GM
authors.lastname: Boxer
authors.forename: R
authors.initials: R
authors.lastname: Boden
authors.forename: R H
authors.initials: RH
authors.lastname: Begent
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000032:analysis; D002250:Carbon Radioisotopes / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000032:analysis; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D018796:Immunoconjugates / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000032:analysis / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use; D008163:Luminescent Measurements; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D016719:Radioimmunodetection / Q000379:methods; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry / Q000379:methods*; D011879:Radiotherapy Dosage; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D002250:Carbon Radioisotopes; D002272:Carcinoembryonic Antigen; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes