Predicting Response to Radioimmunotherapy from the Tumor Microenvironment of Colorectal Carcinomas

Abstract

Solid tumors have a heterogeneous pathophysiology, which directly affects antibody-targeted therapies. Here, we consider the influence of selected tumor parameters on radioimmunotherapy, by comparing the gross biodistribution, microdistribution, and therapeutic efficacy of either radiolabeled or fluorescently labeled antibodies (A5B7 anti-carcinoembryonic antigen antibody and a nonspecific control) after i.v. injection in two contrasting human colorectal xenografts in MF1 nude mice. The LS174T is moderately/poorly differentiated, whereas SW1222 has a well-differentiated glandular structure. Biodistribution studies (1.8 MBq 131 I-labeled A5B7, four mice per group) showed similar gross tumor uptake at 48 h in the two models (25.1% and 24.0% injected dose per gram, respectively). However, in therapy studies (six mice per group), LS174T required a 3-fold increase in dose (18 versus 6 MBq) to equal SW1222 growth inhibition (f55 versus f60 days, respectively). To investigate the basis of this discrepancy, highresolution multifluorescence microscopy was used to study antibody localization in relation to tumor parameters (5 min, 1 and 24 h, four mice per time point). Three-dimensional microvascular corrosion casting and transmission electron microscopy showed further structural differences between xenografts. Vascular supply, overall antigen distribution, and tumor structure varied greatly between models, and were principally responsible for major differences in antibody localization and subsequent therapeutic efficacy. The study shows that multiparameter, high-resolution imaging of both therapeutic and tumor microenvironment is required to comprehend complex antibody-tumor interactions, and to determine which tumor regions are being successfully treated. This will inform the design of optimized clinical trials of single and combined agents, and aid individual patient selection for antibody-targeted therapies. [Cancer Res 2007;67(24):11896-905]

Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours

“…Limitations in antibody diffusion within solid tumour masses have previously been reported for reagents used in the IgG format (Adams and Weiner, 2005;Dennis et al, 2007;El Emir et al, 2007a), mainly in relation to the so-called 'antigen barrier'. In this study, we have used antibodies in SIP format (Borsi et al, 2002;Villa et al, 2008), as this format and similar mini-antibody formats have extensively been shown to offer distinctive advantages both for imaging applications (Leyton et al, 2009);von Lukowicz et al, 2007;Wei et al, 2008) and for radioimmunotherapy of cancer (Berndorff et al, 2005;Tijink et al, 2006;Kenanova et al, 2007;Sauer et al, 2009).…”

“…administration in the tail vein, we used both fluorescence microscopy and radioactivity-based detection methods. As mouse models of human cancer, we chose LS174T and SW1222 tumours: two colorectal cancer models, which have previously been extensively studied using monoclonal antibodies specific to the carcinoembryonic antigen (El Emir et al, 2007a;Fidarova et al, 2008) and with the vascular-targeting anti-EDB antibody L19 (El-Emir et al, 2007b). Figure 6 shows representative results of a multi-colour fluorescence microscopy analysis of serial sections from LS174T tumours, following i.v.…”

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

“…Although we did not have a nonspecific radiolabeled antibody ( 131 I-IgG1/MOPC) control in our studies, we have previously shown no therapeutic effect with a dose of 4 MBq of 131 I-IgG1/ MOPC in SW1222 tumor metastases (16), suggesting that cross-fire irradiation from circulating antibody does not significantly affect tumor growth. Moreover, our current studies show that 10 d after administration, the tumor-to-blood ratio of huA5B7 is approximately 8:1 in SW1222 tumors with minimal blood levels, which supports the hypothesis that the observed therapeutic effects were due to tumor-bound antibody rather than circulating antibody.…”

“…HuA5B7 was provided by UCB Pharma S.A. and labeled with 131 I ( 131 I-huA5B7) (Perkin Elmer, U.K.) using the IODO-GEN (Pierce) method as previously described (16,17). Labeling yield and radiochemical purity were assessed by thin-layer chromatography (silica gel Si60, stationary phase; 80% methanol, mobile phase); antigen binding of the radiolabeled antibody was compared with nonlabeled huA5B7 and assessed by enzyme-linked immunosorbent assay.…”

“…CEA expression was confirmed in all tumor models as previously described (16). Markers of DNA damage response (gH2AX and DNA-PK), cell cycle (phospho-histone H3, cyclin B1), proliferation (Ki-67), and apoptosis (caspase-3) were examined in tumor sections from each group at 2, 6, and 10 d after treatment initiation.…”