Development of A Chimeric Antigen Receptor Targeting C-Type Lectin-Like Molecule-1 for Human Acute Myeloid Leukemia

• Published in: International journal of molecular sciences Vol. 18; no. 11; p. 2259
• Main Authors: Laborda, Eduardo, Mazagova, Magdalena, Shao, Sida, Wang, Xinxin, Quirino, Herlinda, Woods, Ashley K, Hampton, Eric N, Rodgers, David T, Kim, Chan Hyuk, Schultz, Peter G, Young, Travis S
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.10.2017; MDPI
• Subjects: Acute myeloid leukemia; AML; Antigen (tumor-associated); Antigens; CAR-T-cell; CD123 antigen; Chimeric antigen receptors; CLL-1; Communication; hematopoiesis; Hematopoietic stem cells; Immunotherapy; Leukemia; Lymphocytes B; Lymphocytes T; Lymphoma; Molecules; Myeloid leukemia; Myelosuppression; optimization; Patients; Stem cell transplantation; Stem cells; T cell receptors; Toxicity; Xenografts; AML; hematopoiesis; CLL-1; CAR-T-cell; optimization
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms18112259

The treatment of patients with acute myeloid leukemia (AML) with targeted immunotherapy is challenged by the heterogeneity of the disease and a lack of tumor-exclusive antigens. Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma. However, CD33 and CD123 are present on hematopoietic stem cells, and targeting with CAR-T-cells has the potential to elicit long-term myelosuppression. C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a myeloid lineage antigen that is expressed by malignant cells in more than 90% of AML patients. CLL1 is not expressed by healthy Hematopoietic Stem Cells (HSCs), and is therefore a promising target for CAR-T-cell therapy. Here, we describe the development and optimization of an anti-CLL1 CAR-T-cell with potent activity on both AML cell lines and primary patient-derived AML blasts in vitro while sparing healthy HSCs. Furthermore, in a disseminated mouse xenograft model using the CLL1-positive HL60 cell line, these CAR-T-cells completely eradicated tumor, thus supporting CLL1 as a promising target for CAR-T-cells to treat AML while limiting myelosuppressive toxicity.