Early Trial Targeting CLL1-Positive Cells Demonstrates Efficacy in Pediatric AML

Hui Zhang, MD, PhD

Hui Zhang, MD, PhD

A small clinical trial of pediatric patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) showed efficacy and safety with anti-C-type lectin-like molecule (CLL1)-based chimeric antigen receptor (CAR) T cells, according to data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

In an interim analysis from the phase 1/2 trial (ChiCTR1900027684), 10 of 11 patients completely responded to anti-CLL1–based CAR-T cell therapy, with CLL1-positive AML blasts eliminated within 1 month. Six patients achieved complete remission with minimal residual disease (MRD) negativity, added lead investigator Hui Zhang, MD, PhD, an assistant professor at Shanghai Children’s Medical Center and director of Guangzhou Women and Children’s Medical Center at China’s Guangzhou Medical University.

“From all the research shown, we can say that anti-CLL1 based CAR T-cells is a safe therapeutic candidate with manageable CAR T-cell­–associated toxicity for children with R/R AML,” he said. “It is highly effective in targeting CLL1-positive AML cells with superior overall response rate (ORR) relative to conventional/novel targeting compounds.”

In this study, 11 pediatric R/R AML patients aged 2 to 16 years were infused between October 2019 and January 2021 with a second-generation CLL1 CAR-T created in Zhang’s laboratory. Investigators administered a single dose of CLL1 or CLL1-CD33 dual CAR-T cells (target dose: 0.3-1x106/kg) following lymphodepleting conditioning with a cyclophosphamide/fludarabine combination.

Zhang said all 11 patients experienced CAR T-cell expansion in vivo during the first month. Five patients demonstrated persistence of T-cell expansion.

All patients experienced grade 1 to 3 cytokine release syndrome (CRS) but there were no lethal events, Zhang said. All patients experienced myelosuppression, which he said might be due to chemotherapy. Three patients experienced a grade 1/2 hepatic event. No patient experienced cardiac, renal, or gastrointestinal adverse events.

Investigators have suggested that CLL1 is a promising target because it not expressed on normal hematopoietic stem cells (HSCs), but is expressed on 85% to 92% of AML blasts cells and leukemia stem cells.2 In a humanized mouse model, investigators demonstrated that CAR Ts specific for CLL-1 exhibit potent cytokine production and cytotoxicity against CLL-1-expressing AML cell lines without disrupting normal HSCs.

Investigators theorized that developing an anti-CLL1 CAR T therapy would help patients avoid the need for HSC transplant.

In 2020, Zhang published a case study of a 10-year-old girl who presented with an elevated peripheral blood blast percentage while undergoing maintenance treatment for a B-cell ALL relapse. Investigators developed a CAR containing a CLL1-specific single chain variable fragment.3

The patient received lymphodepleting chemotherapy for 4 days before CAR T-cell transfer to enhance in vivo expansion of CAR T-cells. This was followed by a single dose anti-CLL1 CAR-T cells infusion. She experienced Grade 1 to CRS.

After completing CAR T-cell therapy, the patient achieved a complete response and was negative for MRD (<0.1%) on day 29. But the CLL1+ cells were not completely eliminated until 6 months after CAR T-cell therapy. The patient achieved a 10-month response using 1 dose of anti-CLL1 CAR-T monotherapy.


Zhang H, Bu C, Pen Z, et al. The efficacy and safety of anti-CLL1 based CAR-T cells in children with relapsed or refractory acute myeloid leukemia: A multicenter interim analysis. J Clin Oncol. 2021;39(suppl 15):10000. doi:10.1200/JCO.2021.39.15_suppl.10000

Tashiro H, Sauer T, Shum T, et al. Treatment of acute myeloid leukemia with T cells expressing chimeric antigen receptors directed to C-type lectin-like molecule 1. Mol Ther. 2017;25(9):2202-2213. doi:10.1016/j.ymthe.2017.05.024

Zhang H, Gan WT, Hao, WG, et al. Successful ant-CLL1 CAR T-cell therapy in secondary acute myeloid leukemia. Front Oncol. 2020;10:685. Doi:10.3389/fonc.2020.00685

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