Anti-CLL1 Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed/Refractory Acute Myeloid Leukemia

Abstract

Purpose: The survival rate of children with refractory/relapsed acute myeloid leukemia (R/R-AML) by salvage chemotherapy is minimal. Treatment with chimeric antigen receptor T cells (CAR T) has emerged as a novel therapy to improve malignancies treatment. C-type lectin-like molecule 1 (CLL1) is highly expressed on AML stem cells, blast cells, and monocytes, but not on normal hematopoietic stem cells, indicating the therapeutic potential of anti-CLL1 CAR T in AML treatment. This study aimed to test the safety and efficacy of CAR T-cell therapy in R/R-AML. Patients and Methods: Four pediatric patients with R/R-AML were enrolled in the ongoing phase I/II anti-CLL1 CAR T-cell therapy trial. The CAR design was based on an apoptosis-inducing gene, FKBP-caspase 9, to establish a safer CAR (4SCAR) application. Anti-CLL1 CAR was transduced into peripheral blood mononuclear cells of the patients via lentivector 4SCAR, followed by infusion into the recipients after lymphodepletion chemotherapy. Cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and other adverse events were documented. Treatment response was evaluated by morphology and flow cytometry–based minimal residual disease assays. Results: Three patients with R/R-AML achieved complete remission and minimal residual disease negativity, while the other patient remained alive for 5 months. All these patients experienced low-grade and manageable adverse events. Conclusions: On the basis of our single-institution experience, autologous anti-CLL1 CAR T-cell therapy has the potential to be a safe and efficient alternative treatment for children with R/R-AML, and therefore requires further investigation.

Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia

“…CLL-1 is not exclusively expressed on a subset of early hematopoietic cells, AML blasts, and LSCs, but it is also present on healthy monocytes and other immune cells [ 97 , 98 ]. The first clinical applications of CLL-1-targeting CAR-T-cells led to complete remission in three pediatric patients who underwent allo-HCT afterwards [ 99 ]. Further investigations are needed in order to determine if these encouraging outcomes can be achieved in adult AML patients ( Table 1 ).…”

Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives

“…Encouraging results arise from one study in four pediatric patients. Of them, 3 achieved a complete response with 2 MRD responses [ 152 ]. Another approach to avoid the antigens shared in common is targeting the tumor-associated-variant isoforms.…”

Antibody–Drug Conjugates for the Treatment of Acute Pediatric Leukemia

“…No patients achieved objective CR or PR response. Due to the limited tolerability and efficacy, this drug will not move forward in clinical trials, however, CLL-1 remains a promising target for CAR T-cell therapy and future ADCs [74].…”