Abstract 851: Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer murine xenograft models
Authors: Li Chunrong , Mylin Jenna M. , Weichert Jamey P. , Jeffery Justin J. , Weichmann Ashley M. , Nickel Kwang P. , Abel Lindsey J. , Hernandez Reinier , Grudzinski Joseph J. , Marsh Ian R. , Bednarz Bryan P. , Piaskowski Shari M. , Harari Paul M. 
Published: August 2018

Abstract
Radiation therapy is a central treatment modality for head and neck cancer (HNC). Although significant technical advances have been made in delivering highly conformal radiation, normal tissue toxicity remains dose limiting. CLR1404 is a radiolabeled alkylphophocholine analog with theranostic potential as a PET imaging agent (CLR 124, labeled with 124I) and as a radiotherapy agent (CLR 131, labeled with 131I). CLR1404 exhibits preferential uptake in human cancers and provides tumor-selective internal delivery of radiation to complement external beam radiation (XRT) in the treatment of cancer. In this study, we investigated the antitumor effect of CLR 131 in combination with external beam radiation (XRT) in HNC. Using the fluorescently labeled CLR1404 analog, CLR 1501, in conjuntion with fluorescence microscopy and flow cytometry, we first confirmed CLR1404 uptake in 20 HNC cell lines in vitro. Thereafter, we examined CLR 124 uptake and retention in 12 HNC xenograft and patient-derived xenograft (PDX) mouse models via in vivo PET/CT imaging. Our results showed significant tumor uptake and retention of CLR 124 and limited retention in normal tissues. These results were corroborated by ex vivo gamma counting of excised tissues from tumor-bearing mice injected with CLR 131. We further assessed tumor response following single-dose administration of CLR 131 combined with fractionated XRT in 6 HNC xenograft models. Mice treated with non-radiolabeled CLR1404 displayed unchecked tumor progression. Mice treated with either CLR 131 or XRT showed partial inhibiton on tumor growth. Mice treated with CLR 131 combined with XRT exhibited enhanced inhibitory effect on tumor growth compared with either single treatment, confirming augmentation of XRT response by CLR 131 treatment. Targeted radionuclide therapy (TRT) is an attractive approach that employs radiolabeled molecules to specifically deliver radiation to primary and metastatic tumors. We hypothesized that TRT combined with reduced-dose XRT could reduce the normal tissue toxicity profile compared with high-dose XRT alone. In this study, we demonstrated uptake of CLR 131 across multiple HNC cell lines and xenograft models with enhanced antitumor effects when CLR 131 is combined with XRT. These results suggest the potential value of TRT via CLR 131 combined with reduced dose XRT in HNC patients, which will be further tested in a phase I clinical trial.
Citation Format: Chunrong Li, Jenna M. Mylin, Jamey P. Weichert, Justin J. Jeffery, Ashley M. Weichmann, Kwang P. Nickel, Lindsey J. Abel, Reinier Hernandez, Joseph J. Grudzinski, Ian R. Marsh, Bryan P. Bednarz, Shari M. Piaskowski, Paul M. Harari. Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer murine xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 851.