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Intracranial Cannula Implantation for Serial Locoregional Chimeric Antigen Receptor (CAR) T Cell Infusions in Mice
Published on: February 24, 2023
The First-in-Human ENCIT01 Trial Comparing Second- versus Third-Generation L1CAM-specific CAR T Cells in Patients
Navin Pinto1,2,3, Annette Künkele4,5, Catherine M Albert1,2
1Seattle Children's Hospital, Department of Pediatrics, University of Washington, Seattle, Washington.
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, 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.
Conclusions:
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.
Insights
This clinical trial investigated L1CAM-targeted chimeric antigen receptor (CAR) T cells for relapsed neuroblastoma. The treatment was feasible but did not achieve objective responses, suggesting L1CAM may not be an ideal target.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Cancer Research
Background:
- Neuroblastoma is a challenging pediatric cancer with poor outcomes for relapsed or refractory cases.
- Chimeric antigen receptor (CAR) T-cell therapy offers a novel approach for difficult-to-treat cancers.
Purpose of the Study:
- To evaluate the safety and feasibility of L1CAM-targeted CAR T-cells in children with relapsed/refractory neuroblastoma.
- To assess different CAR T-cell constructs (2GS, 3GS, 2GL) in a first-in-human trial (ENCIT-01).
Main Methods:
- The ENCIT-01 trial enrolled 36 patients, with 22 treated across three arms testing different CAR T-cell designs.
- Manufacturing of CAR T-cell products was successful in most patients.
- Dose-escalation was performed to identify dose-limiting toxicities.
Main Results:
- Common toxicities included cytokine release syndrome, skin rash, and hyponatremia, with hyponatremia being dose-limiting.
- Toxicity patterns suggested higher potency for third-generation and long-spacer CAR T-cell constructs.
- No objective anti-tumor responses were observed in treated patients.
Conclusions:
- L1CAM-targeted CAR T-cell therapy is feasible to manufacture in heavily pretreated neuroblastoma patients.
- L1CAM may not be an effective target for neuroblastoma treatment.
- Further engineering strategies are required to improve CAR T-cell therapy efficacy and safety for durable anti-tumor effects.
