Anti-CD33 Chimeric Antigen Receptor Therapy For Acute Myeloid Leukemia

Abstract

Abstract CD33 is a protein expressed on most myeloid leukemia cells and committed myelomonocytic and erythroid progenitor cells, but not on other cell types. This makes it an attractive therapeutic target for acute myeloid leukemia (AML). CD33 positive cells can be specifically targeted for destruction through the use of a chimeric antigen receptor (CAR) expressed on cytotoxic T-lymphocytes (CTL). We have expressed a CD33-specific 41BB/CD3z second generation humanized chimeric antigen receptor (CAR) on human T cells by MSCV retroviral transduction, allowing for the generation of large numbers of CAR-modified CTLs. We assessed the activation and specific lytic ability of these CAR-modified T-cells by using murine and human CD33-transduced cell lines, as well as control CD33 negative lines. Our experiments show that anti-CD33 CAR CTLs specifically kill CD33-transduced 1498 and EL4 cells lines, with greater than 90% killing at 24 hours at a 1:1 effector to target ratio. These CTLs do not kill 1498 and EL4 cells that have not been transduced with CD33. In addition, anti-CD33 CTLs show significant (>90%) killing of multiple CD33 positive AML cell lines, including CHRF-288-11, HU-3, and UT-7, CMK, HL-60, Molm13, and Mv4-11. We have transduced a similar murine anti-CD33 CAR onto mouse CTLs. When these CTLs are injected into C57BL/6 mice with 1498 tumor cells transduced with CD33, the mice have a reduction in tumor burden compared with mice that have been injected with tumor cells and MSCV-negative control CTLs. This data suggests that our anti-CD33 CAR shows promise of therapeutic efficacy in the treatment of AML. Disclosures: No relevant conflicts of interest to declare.