Combination of 90Y-labelled-Cetuximab with fractionated radiotherapy: report on therapy scheduling and curative potential

External beam irradiation (EBRT) can precisely target solid tumors but is limited by the surrounding normal tissue. Radioimmunotherapy mediates additional internal irradiation with the potential to strike also (micro-)metastases. The combination of internal and external radiotherapy (CIERT) is a promising treatment strategy as it potentially combines advantages of both modalities without increasing toxicity. We previously showed that CIERT using 90Y-labelled-Cetuximab ([90Y]Y-Cet) massively increased tumor control probability (TCP) of FaDu xenografts compared to single dose EBRT alone. In the presented project, we investigated CIERT using clinical relevant fractionated EBRT with 30 fractions (fx) over 6 weeks. To model [90Y]Y-Cet uptake and study the best application timing, FaDu-bearing mice were injected with near-infrared-labeled-Cetuximab (NIR-Cet) at different time points during fxEBRT with differing doses. NIR-Cet uptake was longitudinally followed by in vivo optical imaging. From the results we concluded, that low to moderate doses of fxEBRT can enhance Cetuximab uptake. Based on the data, we injected [90Y]Y-Cet after 10 fx of EBRT in ongoing TCP-experiments for testing curative potential of CIERT. First analysis after 90 d observation period show that CIERT massively increase TCP compared to fxEBRT alone or in combination with unlabeled Cetuximab. Even in the group with the lowest external dose (1 Gy/fx, total dose = 30 Gy) plus [90Y]Y-Cet all tumors were permanently controlled. In contrast, the total fxEBRT dose to cure 50% of the tumors without [90Y]Y-Cet injection was 62.8 Gy [57.5, 69.5]. Our results indicate that the combination of radiolabeled therapeutics with fractionated external radiotherapy in a clinical relevant setting has a remarkably potential to improve treatment outcome. An efficient uptake of the drug is a prerequisite for the success of CIERT and may be improved by application of some EBRT dose prior to injection. This scheduling would enable patient stratification via a corresponding PET-tracer during ongoing therapy.