Investigating the Immune Effects of Radiotherapy in Non-Small Cell Lung Cancer-Results of the PD-RAD Study

The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer (NSCLC). However, the concurrent use of radiotherapy (RT) and durvalumab (PACIFIC-2 trial) showed no additional advantage. The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment (TME) to aid in optimizing sequencing of combination therapies.

The PD-RAD trial (ClinicalTrials.gov identifier: NCT03258788) aimed to enroll thirty NSCLC patients receiving radical-intent RT. Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry (mIHC) and high-dimensional mass cytometry (CyTOF), respectively.

Paired biopsies were collected from only three patients (Pts 1, 3 & 4) and blood from four patients (Pts 1-4) before the study was closed early during the COVID-19 pandemic. Programmed Death-Ligand 1 (PD-L1) expression in the TME was raised in Patient 1, who responded well to treatment, and unaltered in two patients with progressive disease. CyTOF analysis revealed elevated circulating classical monocytes, highest in the patient with a good response.

This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint. The hypothesis-generating findings highlight PD-L1⁺ macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response, but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.