Journal Article

DKFZ-2026-02290

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The First-in-Human ENCIT01 Trial Comparing Second- versus Third-Generation L1CAM-specific CAR T Cells in Patients with Primary Refractory or Relapsed Neuroblastoma.

Pinto, N. ; Künkele, A.DKFZ* ; Albert, C. M. ; Taylor, M. R. ; Ullom, H. B. ; Vitanza, N. A. ; Wilson, A. L. ; Cole, B. L. ; Yeung, C. C. S. ; Wright, J. H. ; Huang, W. ; Wendler, J. ; Seidel, K. ; Brown, C. ; Gustafson, J. ; Rawlings-Rhea, S. D. ; Beebe, A. ; Mgebroff, S. ; Gardner, R. A. ; Jensen, M. C. ; Park, J. R.

2026
AACR Philadelphia, Pa. [u.a.]

Abstract: Outcomes for children with relapsed and refractory neuroblastoma are dismal. ENCIT-01 (NCT02311621) was a first-in-human clinical trial for patients with relapsed and refractory neuroblastoma using chimeric antigen receptor (CAR) T cells targeting L1CAM, an adhesion molecule that is overexpressed in neuroblastoma with limited normal tissue expression.This trial evaluated three different CAR constructs: a short-spacer second-generation 4-1BB CAR (2GS, arm A), a short-spacer third-generation 4-1BB + CD28 CAR (3GS, arm B), and a long-spacer second-generation 4-1BB CAR (2GL, arm C).Thirty-six patients were enrolled, of whom 22 were treated (arm A/2GS n = 11, arm B/3GS n = 8, and arm C/2GL n = 3). Thirty-four of 36 patients had a CAR T-cell product successfully manufactured. Cytokine release syndrome, skin rash, and hyponatremia were common ≥ grade 2 toxicities. Hyponatremia was dose-limiting in three patients [dose level (DL); DL5 arm A/2GS, DL3 arm B/3GS, and DL2 arm C/2GL]. Patterns of toxicity appeared at lower DLs on arms B and C compared with arm A, suggesting differential potency of the third generation and long-spacer products. No objective responses were seen. Correlative analyses demonstrated CAR T-cell presence in tumor and skin, with evidence of macrophage tumor infiltration.Although feasible to manufacture in a heavily pretreated population, L1CAM may not be an appropriate target in neuroblastoma. Additional engineering strategies may be needed to prevent toxicity and provide durable antitumor effects.

Keyword(s): Humans (MeSH) ; Neuroblastoma: therapy (MeSH) ; Neuroblastoma: immunology (MeSH) ; Neuroblastoma: pathology (MeSH) ; Female (MeSH) ; Neural Cell Adhesion Molecule L1: immunology (MeSH) ; Neural Cell Adhesion Molecule L1: antagonists & inhibitors (MeSH) ; Male (MeSH) ; Child (MeSH) ; Child, Preschool (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Receptors, Chimeric Antigen: genetics (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: metabolism (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Immunotherapy, Adoptive: adverse effects (MeSH) ; Neoplasm Recurrence, Local: immunology (MeSH) ; Neoplasm Recurrence, Local: therapy (MeSH) ; Neoplasm Recurrence, Local: pathology (MeSH) ; Infant (MeSH) ; Adolescent (MeSH) ; Treatment Outcome (MeSH) ; Receptors, Antigen, T-Cell: genetics (MeSH) ; Receptors, Antigen, T-Cell: immunology (MeSH) ; Neural Cell Adhesion Molecule L1 ; Receptors, Chimeric Antigen ; L1CAM protein, human ; Receptors, Antigen, T-Cell

Note: #DKTKZFB9#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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