Radiopharmaceuticals enhance CAR T-cells against radio-sensitive and radio-resistant neuroblastoma by tumor sensitization and TME remodeling [scRNA-Seq]

Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [67Cu]Cu-LLP2A and find that it potentiated the anti-tumor activity of CAR T-cells in radio-sensitive and radio-resistant NB models via distinct mechanisms.

In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T-cell efficacy through pro-immune pathways, most notably via the TNFα pathway, leading to paracrine activation of T-cells. In radio-resistant NB, RPT improves CAR T-cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8⁺ GZMB⁺ and CD4⁺ GZMB+ CAR T-cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T-cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.