Low-dose radiation by radiopharmaceutical therapy enhances GD2 <i>TRAC</i> -CAR T cell efficacy in localized neuroblastoma
Quaovi H. Sodji, Amanda G. Shea, Dan Cappabianca, Matthew H. Forsberg, Jens C. Eickhoff, Malick Bio Idrissou, Andy S. Ollendorff, Ohyun Kwon, Irene M. Ong, Reinier Hernandez, Jamey P. Weichert, Bryan P. Bednarz, Krishanu Saha, Paul M. Sondel, Christian M. Capitini, Zachary S. Morris
Abstract
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 TRAC- CAR T cells to improve outcomes in neuroblastoma. We found that in the localized model of neuroblastoma, low-dose radiation delivered by 177 Lu-NM600, an alkylphosphocholine mimetic RPT agent, followed 9 days later by GD2 TRAC- CAR T cells led to complete tumor regression. Irradiation of neuroblastoma before GD2 TRAC- 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.