Low-dose radiation by radiopharmaceutical therapy enhances GD2 <i>TRAC</i> -CAR T cell efficacy in localized neuroblastoma

Chimeric antigen receptor (CAR) T cells have limited efficacy against solid tumors including neuroblastoma. Here, we evaluated whether low-dose radiation delivered by radiopharmaceutical therapy (RPT), known to potentiate immune checkpoint inhibitors, can synergize with CRISPR-edited GD2 <i>TRAC-</i>CAR T cells to improve outcomes in neuroblastoma. We found that in the localized model of neuroblastoma, low-dose radiation delivered by ¹⁷⁷Lu-NM600, an alkylphosphocholine mimetic RPT agent, followed 9 days later by GD2 <i>TRAC-</i>CAR T cells led to complete tumor regression. Irradiation of neuroblastoma before GD2 <i>TRAC-</i>CAR T cells enhanced the release by CAR T cells of perforin, granzyme B, tumor necrosis factor-α, and interleukin-7 while abrogating transforming growth factor-β1. Low-dose RPT up-regulated the death receptor Fas on neuroblastoma, potentially enabling CAR-independent killing. This suggests that low-dose RPT can enhance suboptimal CAR T cell efficacy against solid tumors. However, optimization of radiation dose and timing may be needed for each patient and RPT agent to account for varied tumor radiosensitivity and dosimetry.