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

Area of Science:

• Oncology
• Radiotherapy
• Immunotherapy

Background:

• Colorectal cancer (CRC) is a leading cause of cancer mortality globally.
• External beam radiotherapy (RT) is used for CRC, but dose escalation is limited by toxicity to surrounding organs.
• Targeted Radionuclide Therapy (TRT) offers selective tumor cell targeting via molecular vectors and therapeutic radionuclides.

Purpose of the Study:

• To provide proof-of-concept for combining in vivo RT with anti-PDL1-targeted TRT.
• To evaluate the efficacy of combining RT with anti-PDL1 TRT delivered via an anti-PDL1 antibody.

Main Methods:

• An anti-PDL1 monoclonal antibody (mAb) was bioconjugated and radiolabeled with ¹¹¹In (imaging) or ¹⁷⁷Lu (therapy).
• Biodistribution and TRT efficacy were assessed in CT26 tumor-bearing mice post-RT.
• Epitope saturation assays were performed using excess unlabeled anti-PDL1 mAb.

Main Results:

• RT increased PDL1 expression in tumors, enhancing intratumoral uptake of radiolabeled anti-PDL1 mAb.
• High spleen uptake of the radiolabeled antibody reduced TRT efficacy by decreasing CD8+ T lymphocyte infiltration.
• Epitope saturation significantly reduced spleen uptake while preserving tumor uptake, restoring combination therapy efficacy.

Conclusions:

• The combination of RT and anti-PDL1 TRT demonstrates synergistic potential in colorectal cancer.
• Blocking anti-PDL1 mAb uptake in the spleen is essential for maximizing the therapeutic benefit of this combination therapy.