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

  • Sci Adv. 2025 Jun 6;11(23):eadu4417. doi: 10.1126/sciadv.adu4417.
Quaovi H Sodji  1  2 ,  Amanda Shea  1 ,  Dan Cappabianca  1 ,  Matthew H Forsberg  3 ,  Jens C Eickhoff  4 ,  Malick Bio Idrissou  5 ,  Andy S Ollendorff  1 ,  Ohyun Kwon  5 ,  Irene M Ong  4  6 ,  Reinier Hernandez  2  5 ,  Jamey Weichert  2  5  7 ,  Bryan P Bednarz  2  5 ,  Krishanu Saha  2  8 ,  Paul M Sondel  1  2  3 ,  Christian M Capitini  2  3 ,  Zachary S Morris  1  2
Affiliations
  • 1. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 2. Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
  • 3. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 4. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 5. Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 6. Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 7. Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • 8. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
PMID: 40465728 DOI: 10.1126/sciadv.adu4417
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 177Lu-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.

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