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Publications

Journal Article Ahead of print

PubMed: 42362068 DOI: 10.1016/j.ijrobp.2026.06.3061

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

Int J Radiat Oncol Biol Phys

Authors: Pierre-Simon Bellaye, Alexia Tavares, Riad Ladjohounlou, Mathieu Moreau, Claire Bernhard, Alexandre Dias, Michael Claron, Lisa Froidurot, Mélanie Guillemin, Bertrand Collin, Franck Denat, Gilles Truc, Alexandre Cochet, Jérémy Baude, Céline Mirjolet

Affiliations

  • Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, IRIS Unit, IMATHERA, UMS INSERM 58 and CTM, UMR INSERM 1231, HSP-pathies team, 21000 Dijon, France.
  • Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, X-RAIN Unit, IMATHERA, UMS INSERM 58 and CTM, UMR INSERM 1231, TIRECs team, 21000 Dijon, France.
  • Université Bourgogne Europe, CNRS, Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB, UMR CNRS 6302), 9 avenue Alain Savary, 21078 Dijon Cedex, France.
  • Université Bourgogne Europe, CNRS, Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB, UMR CNRS 6302), 9 avenue Alain Savary, 21078 Dijon Cedex, France; Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, IMATHERA, IRIS Unit, UMS INSERM 58, 21000 Dijon, France.
  • Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, IMATHERA, IRIS Unit, UMS INSERM 58, 21000 Dijon, France.
  • Université Bourgogne Europe, CNRS, Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB, UMR CNRS 6302), 9 avenue Alain Savary, 21078 Dijon Cedex, France; Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Radiation Oncology Department, 21000 Dijon, France.
  • Université Bourgogne Europe, CNRS, Institut de Chimie Moléculaire de l'Université de Bourgogne (ICMUB, UMR CNRS 6302), 9 avenue Alain Savary, 21078 Dijon Cedex, France; Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Nuclear Medicine Department, 21000 Dijon, France.
  • Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, X-RAIN Unit, IMATHERA, UMS INSERM 58 and CTM, UMR INSERM 1231, TIRECs team, 21000 Dijon, France; Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Radiation Oncology Department, 21000 Dijon, France.
  • Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, X-RAIN Unit, IMATHERA, UMS INSERM 58 and CTM, UMR INSERM 1231, TIRECs team, 21000 Dijon, France.

Abstract

PURPOSE

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.

METHODS AND MATERIALS

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.

RESULTS

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.

CONCLUSIONS

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.

MeSH

Radiotherapy, Cells, Neoplasms, Colon, Therapeutics, Colorectal Neoplasms, Spleen