The first-in-human ENCIT01 trial comparing second- versus third-generation L1CAM-specific CAR T cells in patients with primary refractory or relapsed neuroblastoma

PURPOSE: 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. PATIENTS AND METHODS: 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). RESULTS: Thirty-six patients were enrolled and 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 3 patients (DL5 Arm A/2GS, DL3 Arm B/3GS and DL2 Arm C/2GL). Patterns of toxicity appeared at lower dose levels on Arm B and Arm C compared to 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. CONCLUSIONS: While 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 anti-tumor effects.

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Publication Details

Journal
Clinical Cancer Research
Published
2026-06-18
DOI
https://doi.org/10.1158/1078-0432.ccr-26-0009
Primary Topic
CAR-T cell therapy research
Type
article
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article

The first-in-human ENCIT01 trial comparing second- versus third-generation L1CAM-specific CAR T cells in patients with primary refractory or relapsed neuroblastoma

Michael C. Jensen, Annette Künkele, Julie R. Park, Joshua A. Gustafson et al.
Clinical Cancer Research
CAR-T cell therapy research
article

The first-in-human ENCIT01 trial comparing second- versus third-generation L1CAM-specific CAR T cells in patients with primary refractory or relapsed neuroblastoma

Michael C. Jensen, Annette Künkele, Julie R. Park, Joshua A. Gustafson, Ashley Wilson, Nicholas A. Vitanza, Catherine M. Albert, Stephanie Rawlings-Rhea, Christopher Brown, Wenjun Huang, Bonnie Cole, Cecilia C.S. Yeung, Jason Wendler, Rebecca Gardner, Stephanie Mgebroff, Navin Pinto, Kristy Seidel, Mallory Taylor, Adam Beebe, Heidi B. Ullom, Jocelyn H. Wright
article en

Abstract

PURPOSE: 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. PATIENTS AND METHODS: 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). RESULTS: Thirty-six patients were enrolled and 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 3 patients (DL5 Arm A/2GS, DL3 Arm B/3GS and DL2 Arm C/2GL). Patterns of toxicity appeared at lower dose levels on Arm B and Arm C compared to 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. CONCLUSIONS: While 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 anti-tumor effects.

Clinical Cancer Research
Center for Infectious Disease Research (US), St. Jude Children's Research Hospital (US), Children’s Institute (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Fred Hutch Cancer Center (US), Seattle Children's Hospital (US), Charité - Universitätsmedizin Berlin (DE), University of Colorado Denver (US)
Openalex Percentile: Top 8%
CAR-T cell therapy research
DOISourceOpenAlex
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