Donor-derived GD2-specific CAR T cells in relapsed or refractory neuroblastoma

Nat Med. 2025 Mar;31(3):849-860. doi: 10.1038/s41591-024-03449-x. Epub 2025 Jan 15.

Abstract

Allogeneic chimeric antigen receptor (CAR) T cells targeting disialoganglioside-GD2 (ALLO_GD2-CART01) could be a therapeutic option for patients with relapsed or refractory, high-risk neuroblastoma (r/r HR-NB) whose tumors did not respond to autologous GD2-CART01 or who have profound lymphopenia. We present a case series of five children with HR-NB refractory to more than three different lines of therapy who received ALLO_GD2-CART01 in a hospital exemption setting. Four of them had previously received allogeneic hematopoietic stem cell transplantation. All patients experienced grade 2 or 3 cytokine release syndrome and one grade 2 neurotoxicity. Moderate acute graft-versus-host-disease occurred in four patients. ALLO_GD2-CART01 persisted for >6 weeks. Post-treatment, two complete responses were achieved and one maintained; in addition, one partial response and one stable disease were observed. Comparing the transcriptomic profiles obtained by RNA sequencing analyses of drug products with patient-matched, peripheral blood ALLO_GD2-CART01 collected at expansion, we found upregulation of genes associated with T cell activation and migration. In addition, after infusion, transcriptomic signaling analysis showed enrichment of genes involved in response to decreased oxygen levels, humoral immune response, cell polarization and immune-synapse formation. In comparison to autologous CAR T cells, ALLO_GD2-CAR T cells were characterized by pathways associated with T cell proliferation, immune-synapse formation and cell chemotaxis. The safety and efficacy of ALLO_GD2-CART01 in children with r/r HR-NB deserve further investigation in a prospective trial.

MeSH terms

  • Child
  • Child, Preschool
  • Female
  • Gangliosides* / immunology
  • Graft vs Host Disease / immunology
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / methods
  • Infant
  • Male
  • Neoplasm Recurrence, Local / immunology
  • Neoplasm Recurrence, Local / therapy
  • Neuroblastoma* / genetics
  • Neuroblastoma* / immunology
  • Neuroblastoma* / pathology
  • Neuroblastoma* / therapy
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / immunology
  • T-Lymphocytes* / immunology

Substances

  • Gangliosides
  • Receptors, Chimeric Antigen
  • ganglioside, GD2
  • Receptors, Antigen, T-Cell