First-in-human comparison of second- versus third-generation L1CAM-specific CAR T cells in patients with primary refractory or relapsed neuroblastoma

Author:

Pinto Navin1ORCID,Künkele Annette2ORCID,Albert Catherine3,Taylor Mallory3ORCID,Ullom Heidi4,Wilson Ashley5,Huang Wenjun3ORCID,Wendler Jason5,Seidel Kristy3,Brown Christopher3,Gustafson Joshua3ORCID,Rawlings-Rhea Stephanie3,Beebe Adam5,Mgebroff Stephanie5,Gardner Rebecca6,Jensen Michael3ORCID,Park Julie7ORCID

Affiliation:

1. University of Colorado School of Medicine

2. Charité Universitätsmedizin Berlin

3. Seattle Children's Research Institute

4. Seattle Children's Hospital

5. Seattle Children's Therapeutics

6. St. Jude Children's Research Hospital

7. St Jude Children's Research Hospital

Abstract

Abstract Outcomes for children with relapsed and refractory neuroblastoma are dismal. ENCIT-01 is our first-in-human experience in patients with relapsed and refractory neuroblastoma using chimeric antigen receptor (CAR) T cells targeting L1-CAM, 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 (Arm A), a short spacer third-generation 4-1BB+CD28 CAR (Arm B) and a long spacer second-generation 4-1BB CAR (Arm C). Thirty-six patients were enrolled and 22 were treated (Arm A n=11, Arm B n=8 and Arm C n=3). Cytokine-release syndrome, skin rash and dose-limiting hyponatremia were recurrently encountered toxicities. Patterns of toxicity appeared at lower dose levels on Arm B and Arm C compared to Arm A, suggesting enhanced potency of the third generation and long spacer products. No objective responses were seen. Correlative analyses demonstrated CAR T cells infiltration into tumor and skin, with evidence of macrophage tumor infiltration. In addition, enhanced CD107a production in the third-generation products when compared to patient matched second generation product, potentially explaining the observation of toxicities at lower dose levels. While feasible to manufacture in a heavily pretreated population, additional engineering safety of L1CAM CAR T cells and/or strategies to target the immunosuppressive tumor microenvironment may be needed to prevent toxicity and provide durable anti-tumor effects.

Publisher

Research Square Platform LLC

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. GD2 targeting CAR T cells for neuroblastoma;EJC Paediatric Oncology;2024-12

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