2. Academic Validation
  3. Low-dose radiation by radiopharmaceutical therapy enhances GD2 TRAC-CAR T cell efficacy in localized neuroblastoma

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

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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