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http://purl.uniprot.org/citations/27390347http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
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Purpose

The identification and vetting of cell surface tumor-restricted epitopes for chimeric antigen receptor (CAR)-redirected T-cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation-dependent tumor-specific epitope recognized by the CE7 monoclonal antibody.

Experimental design

CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a preclinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed.

Results

CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 1 × 108/kg CE7-CAR+ CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4+ and CD8+ CE7-CAR T-cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T-cell products demonstrated in vitro and in vivo antitumor activity.

Conclusions

Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466-77. ©2016 AACR."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.org/dc/terms/identifier"doi:10.1158/1078-0432.ccr-16-0354"xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Berger C."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Brown C."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Berger M."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Johnson A.J."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Finn L.S."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Park J.R."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Chang C.A."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Jensen M.C."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Kunkele A."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Taraseviciute A."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Finney O."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Mgebroff S."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/author"Rolczynski L.S."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/date"2017"xsd:gYear
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/name"Clin Cancer Res"xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/pages"466-477"xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/title"Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma: CE7 Epitope Target Safety and Product Manufacturing Feasibility."xsd:string
http://purl.uniprot.org/citations/27390347http://purl.uniprot.org/core/volume"23"xsd:string
http://purl.uniprot.org/citations/27390347http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/27390347
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