Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma
- 25 November 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (571)
- https://doi.org/10.1126/scitranslmed.abd6169
Abstract
The reprogramming of a patient's immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving >= 10(8)/meter(2) CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.Funding Information
- Wellcome (102803/Z/13/Z)
- Cancer Research UK (Trial, manufacturer and pharmacodynamic assay agreements)
- Action Medical Research (GN2400)
- Great Ormond Street Hospital Charity (VS0118)
- Great Ormond Street Hospital Charity (W1134)
- Neuroblastoma UK (N/A)
- Research In Childhood Cancer (One off donation)
- NIHR Great Ormond Street Biomedical Research Centre (N/A)
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