External Beam Radiotherapy Primes PDL1-Targeted Radionuclide Therapy in Preclinical Colorectal Cancer Model.

Abstract

Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies worldwide. Although external beam radiotherapy (RT) plays a growing role in primary and metastatic CRC, dose escalation may remain limited due to the high dose received by neighboring organs which may cause toxicity. Targeted Radionuclide Therapy (TRT) selectively delivers cytotoxic radiation to tumor cells through a molecular vector that targets a specific protein overexpressed by cancer cells, and is linked to a therapeutic radionuclide. The present study aims to provide proof-of-concept for combining in vivo RT with anti-PDL1-targeted TRT delivered via an anti-PDL1 antibody. An anti-PDL1 monocolonal antibody (mAb) was bioconjugated with a DOTAGA chelating agent and radiolabeled with either indium-111 (¹¹¹In) for imaging purposes (SPECT imaging) or lutetium-177 (¹⁷⁷Lu) for therapeutic purposes (TRT). ¹¹¹In-mAb-PDL1 biodistribution and TRT evaluation were performed in CT26 tumor-bearing mice six days after RT (8Gy) by i.v. injection of ¹¹¹In-mAb-PDL1 or ¹⁷⁷Lu-mAb-PDL1. Epitope saturation assay was performed by co-administrating an excess of unconjugated mAb-PDL1. RT induced a significant increase in PDL1 expression in colon tumors in vivo enhancing the intratumoral uptake of radiolabeled anti-PDL1 mAb with ¹¹¹In or ¹⁷⁷Lu. A high uptake of radiolabeled anti-PDL1 mAb was found in the spleen that hampered the efficacy of the combination of RT with anti-PDL1 TRT by inducing a significant decrease in CD8⁺ T lymphocytes infiltration in tumors. Epitope-saturation with a 15-fold excess of unlabeled anti-PDL1 mAb significantly reduced the spleen uptake of ¹¹¹In-mAb-PDL1 while preserving tumor uptake. This restored the efficacy of the combination of RT with ¹⁷⁷Lu-mAb-PDL1, compared to both treatments alone. The combination of RT and anti-PDL1 TRT shows promising synergistic effects but it requires the blockade of anti-PDL1 mAb uptake in the spleen.