CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia

Abstract

BackgroundAcute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment.MethodsWe tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells.ResultsThe CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression.ConclusionsCLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0553-5) contains supplementary material, which is available to authorized users.

Revisiting CLEC12A as leukaemic stem cell marker in AML: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy

“…In addition, we have recently shown the relevance of the marker in myelodysplastic syndrome (MDS) and pointed out important differences in the applicability of the marker in these biologically different disease entities (Toft-Petersen et al, 2016). Given this, the CLEC12A receptor is an attractive treatment target in AML, and current developments in this regard include both CLEC12A-CD3 bispecific antibodies (Lu et al, 2014;Leong et al, 2017) and chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells) directed against CLEC12A (Laborda et al, 2017;Tashiro et al, 2017;Wang et al, 2018) and, most recently, the development of a novel antibody-drug conjugate (Jiang et al, 2018).…”

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

“…An additional limitation in AML has been the lack of ideal target antigens, which hinders the use of ADCC, T cell engaging techniques, and CAR (chimeric antigen receptor) T‐cells. Nonetheless, there are numerous ongoing trials investigating the role of CAR T‐cells for AML, with major targets including CD33, CD123, CLL‐1, and FLT3 . Similarly, T‐cell engaging techniques are now being used in AML, mostly targeting CD33 and CD123 .…”

The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target

“…Much the same applies to the developing literature on targeting the CLEC12A receptor (Zhao et al , ; Lu et al , ; Laborda et al , ; Leong et al , ; Tashiro et al , ; Wang et al , ), which has also been shown to be absent on the most immature HSPCs in normal bone marrow (van Rhenen et al , ; Bill et al , ). Recent efforts in targeting this marker include the development of cytotoxic monoclonal antibodies (Zhao et al , ) and CLEC12A‐CD3 bispecific antibodies (Lu et al , ; Leong et al , ).…”

“…A first‐in‐human phase 1 clinical trial of a bispecific CLEC12A‐CD3 antibody for the treatment of relapsed/refractory AML or previously untreated elderly AML patients is currently recruiting (NCT03038230). In addition, the recently developed chimeric antigen receptor (CAR) engineered T cells (CAR‐T cells) directed against CLEC12A (Laborda et al , , Tashiro et al , , Wang et al, ) and toxin‐conjugated antibodies also seem promising (Jiang et al , ). Taken together – and given the success of other antibody‐based initiatives, most prominently rituximab – this line of anti‐LSC targeting is definitely one to follow.…”