Combination of ¹⁷⁷Lu-labeled anti-L1CAM mAb chCE7 and paclitaxed improved survival and enhanced tumor uptake of the radio-immuno-conjugate in nude mice bearing human ovarian cancer

Full text of publication follows. Aim: Recently we could show that radioimmunotherapy with ¹⁷⁷Lu-labeled anti-L1CAM monoclonal antibody chCE7 is a valuable option for treatment of ovarian cancer [Fischer et al. Int J Cancer 2012, 130:2715]. Based on these results we investigated if the efficacy of radioimmunotherapy can be improved by combination with paclitaxel (PTX). Furthermore in vitro data of induced G2/M phase cell cycle arrest and cell growth upon different combination treatment conditions were collated. Material and Methods: Cell viability for different treatment conditions was measured in vitro by MTT assays and cell cycle arrest by flow cytometry. In vivo therapy was performed in nude mice (n=8) with subcutaneous IGROV1 ovarian cancer xenografts. Mice were injected with a single dose of 6 MBq ¹⁷⁷Lu-chCE7 alone or in combination with 600 μg PTX administered 24 h post radioimmunotherapy. Control groups received an accordant treatment scheme containing an unspecific ¹⁷⁷Lu-labeled antibody in combination with PTX. Tumor growth delay was measured and mice reaching a defined end point were killed. Biodistribution (n=4) and SPECT images were acquired post treatments with injections of 2 MBq ¹⁷⁷Lu-chCE7 alone or in combination with 600 μg PTX 24 h post radio-immuno-conjugate administration. Results: In vitro combination revealed a decreased cell viability of ovarian carcinoma cells compared to monotherapy treatments. Quantification of cell cycle arrest of PTX pretreated cells resulted in 65 % of cells being arrested in the radiosensitive G2/M-phase peaking at 24 h post PTX treatment with half maximal inhibitory concentration (IC50). In vivo combination therapy of ¹⁷⁷Lu-chCE7 and PTX reduced tumor burden with a significant decrease in tumor size of 80% (±8,2%) compared to mono therapies (16 days post treatment; P<0.05). Median survival of control groups varied between 21 and 34 days whereas 6 out of 8 mice are still alive after 54 days in the combination treatment group. Biodistribution studies revealed a significant higher tumor uptake of ¹⁷⁷Lu-chCE7 72 h post injection by 12% (P<0.05) in mice treated in combination with PTX. In addition SPECT scans and micro-autoradiography studies confirmed a higher uptake at the tumor site. Conclusion: Combination of ¹⁷⁷Lu-chCE7 and paclitaxel is a promising treatment modality resulting in a prolonged survival of tumor-bearing nude mice compared to mono-therapies. Whether enhanced tumor uptake is a consequence of increased blood vessel permeability caused by PTX treatment is subject of current investigations. (authors)