Abstract
Abstract Table of Contents * Pretargeted radioimmunotherapy of an anti-CEA bispecific antibody and 177Lu-labeled peptide: a phase I study in patients with advanced colorectal cancer * Abstract Objectives: Pretargeted radioimmunotherapy (PRIT) with bispecific monoclonal antibodies (bsMAb) in combination with a radiolabeled peptide reduces the radiation dose of conventional RIT to normal tissues by rapid tumor targeting and fast blood clearance of the radiolabeled molecule. In this phase I trial, PRIT was investigated in 20 patients with advanced colorectal cancer (CRC), using a humanized recombinant bsMAb, TF2, targeting carcinoembryonic antigen (CEACAM5) and the hapten-peptide, IMP288, which was radiolabeled with177Lu. The safety, pharmacokinetics, and tumor targeting of these agents were studied, by optimizing the dose schedule of the pretargeting system. Methods: We included four cohorts with five patients per cohort. We studied the interval between the bsMAb and peptide administration and its consequences for the blood clearance of the radiolabeled peptide (cohort 1: 5 days interval vs next cohorts: 1 day). We escalated TF2 dose to saturate tumor antigens (cohort 3: 150 mg TF2, vs other cohorts: 75 mg). Furthermore, we investigated the effect of labelling the same radioactivity doses to a lower peptide dose, which ideally would increase the fractional targeting to the tumors (cohort 4: 25 µg IMP288 vs other cohorts: 100 µg) A pre-therapy cycle with 111In-labeled IMP288 was used to predict the pharmacokinetics and tumor targeting of 177Lu-IMP288, and to assure safety of high 177Lu activity doses (3.7 GBq in cohort 1 and ≤ 7.4 GBq in cohorts 2-4). Toxicity was determined by NCI-CTC v3.0. Whole-body planar and SPECT images were acquired. Results: Toxicity was generally very mild, with only two patients showing grade 3-4 thrombocytopenia, and one with grade 3 dyspnea. Dose escalation did not increase toxicity. Rapid localization of the radiolabeled peptide in the tumor lesions was clearly visualized with scintigraphy within 1 h of injection, with excellent tumor-to-normal tissue ratios (>20 at 24 h after injection in all cohorts). Low absorbed radiation doses to the red bone marrow (<0.3 Gy) and kidneys (<6 Gy) were calculated for all cohorts. TF2 and 111In/177Lu-IMP288 cleared rapidly from the blood (<2%ID in the blood 1 day p.i. in all cohorts). Conclusion: These first results in man show that CEACAM5-expressing CRC can be safely, specifically and rapidly targeted with TF2 and 177Lu-IMP288, with limited toxicity, by pretargeted radioimmunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1755. doi:1538-7445.AM2012-1755
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