Journal
NATURE MEDICINE
Volume 25, Issue 9, Pages 1408-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0549-5
Keywords
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Funding
- Children with Cancer UK
- Great Ormond St Children's Charity
- JP Moulton Foundation
- National Institute for Health Research Biomedical Research Centres at Great Ormond Street Hospital for Children NHS Foundation Trust
- University College London Hospital
- King's Health Partners
- University College London
- NIHR [514413]
- GOSH-CC [543539]
- Stylian Petrov Foundation
- UK National Institute of Health Research University College London Hospital Biomedical Research Centre
- CRUK [C604/A25135]
- Experimental Cancer Medicine Centre [C30122/A25150]
- NIHR Biomedical Research Centres (BRC) based at King's Health Partners
- JP Moulton Foundation [522356]
- European Union FP7 consortium ATECT [602239]
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Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)(1-5), but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19(-) clones. Some factors, including the choice of single-chain spacer(6) and extracellular(7) and costimulatory domains(8), have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses(9-11). We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies(1-4). CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.
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