Abstract 4082: Preclinical assessment of external or targeted radiotherapy in combination with immunotherapies and co-development of companion imaging diagnostic
Authors: Raguin Olivier , Mirjolet Céline , Bernhard Claire , Provent Peggy , Collin Bertrand , Denat Franck , Viviani Fabrice , Cochet Alexandre , Berthet Cyril 
Published: August 2019

Abstract
Immunotherapies have proven to be highly efficient for cancer treatments and combination with either internal vectorized or external radiotherapies can enhance this efficacy through notably increasing tumor immune infiltrate. The clinical evaluation of such combination therapies requires expertise and exquisite processes in multiple fields, immunotherapy, radiotherapy and nuclear medicine. Similarly, this applies into preclinical settings for assessing proof of concept of novel combinations. Herein, we will present our preclinical evaluation process to combine external or internal (i.e. lutetium-177 radiolabeled molecule) radiotherapy with immunotherapies that include radiochemistry, target expression in tissue by autoradiography, in vitro binding evaluation, in vivo tolerance and activity based on single or fractionated treatment doses. The targeted radiotherapy (TRT) is a systemic target-based approach combining a high-affinity receptor-binding ligand radiolabeled with a high-energy beta-emitting radionuclide whereas external 3D image guided radiotherapy targets the shape of the tumors very precisely. Combination studies with immunotherapies in preclinical setting require the selection of appropriate and relevant syngenic or humanized mouse models, driven by target expression, radioresistance (i.e hypoxia), and tumor immune infiltrate (lymphocyte CD8, macrophage etc.). In addition, the therapeutic evaluation should take into consideration the tolerance related to ionizing radiations, the scheduling of treatment (cumulated dose, fractionation), antitumor immune response and monitoring of immune checkpoint target expression. As nuclear imaging is a powerful tool to monitor and predict in vivo target expression and treatment efficacy, TRT is systematically developed in parallel of a PET or SPECT companion diagnostic to visualize and quantify the target expression prior to the treatment with a therapeutic radiolabeled drug. It necessitates the development of radiolabeling processes for either therapeutic or diagnostic purposes and is then performed concomitantly using appropriate bioconjugation strategies suited for theranostic pairs of radionuclides .We will present our recent results that highlight the importance to optimize the external radiotherapy schedule to improve the efficacy and synergistic effect of the association radiotherapy/immunotherapy such as anti-PDL1. Similarly, it is of high interest to combine 177Lu-labeled molecule with immune checkpoint inhibitors in various solid tumors. Transversal skills are mandatory to perform such models and experiments, all being conducted in a dedicated facility for external 3D image guided radiotherapy (SARRP), radiochemistry (hot cells, 177Lu, 68Ga, 64Cu, 89Zr, 111In) and pharmaco-imaging (PET, SPECT, MRI, CT, and optical).
Citation Format: Olivier Raguin, Céline Mirjolet, Claire Bernhard, Peggy Provent, Bertrand Collin, Franck Denat, Fabrice Viviani, Alexandre Cochet, Cyril Berthet. Preclinical assessment of external or targeted radiotherapy in combination with immunotherapies and co-development of companion imaging diagnostic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4082.