Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape

CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA⁺ but also sLeA^– tumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigen-negative tumor relapse. RNA sequencing analysis of low-dose radiation-exposed tumors reveals the transcriptional signature of cells highly sensitive to TRAIL-mediated death. We find that sLeA-targeted CAR T cells produce TRAIL upon engaging sLeA⁺ tumor cells, and eliminate sLeA⁻ tumor cells previously exposed to systemic or local low-dose radiation in a TRAIL-dependent manner. These findings enhance the prospects for successfully applying CAR therapy to heterogeneous solid tumors. Local radiation is integral to many tumors’ standard of care and can be easily implemented as a CAR conditioning regimen. Tumor antigen escape is a major challenge for CAR T cell therapy, especially for solid tumors. DeSelm et al. demonstrate how low-dose radiation conditioning sensitizes pancreatic cancer to CAR T cell killing and allows CAR T cells to eliminate heterogeneous tumors.