Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia

• Published in: Haematologica (Roma) Vol. 100; no. 3; pp. 336 - 344
• Main Authors: O'Hear, Carol, Heiber, Joshua F, Schubert, Ingo, Fey, Georg, Geiger, Terrence L
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.03.2015
• Subjects: Animals; Bone Marrow - immunology; Bone Marrow - pathology; Cell Line, Tumor; Coculture Techniques; Cytotoxicity, Immunologic; Gene Expression; Humans; Immunotherapy, Adoptive - methods; Interleukin Receptor Common gamma Subunit - deficiency; Interleukin Receptor Common gamma Subunit - genetics; Interleukin Receptor Common gamma Subunit - immunology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - pathology; Leukemia, Myeloid, Acute - therapy; Liver - immunology; Liver - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Mutant Chimeric Proteins - genetics; Mutant Chimeric Proteins - immunology; Plasmids - chemistry; Plasmids - genetics; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Sialic Acid Binding Ig-like Lectin 3 - antagonists & inhibitors; Sialic Acid Binding Ig-like Lectin 3 - genetics; Sialic Acid Binding Ig-like Lectin 3 - immunology; Spleen - immunology; Spleen - pathology; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - transplantation; Transfection
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2014.112748

Current therapies for acute myeloid leukemia are associated with high failure and relapse rates. Adoptive immunotherapies, which have shown promise in the treatment of hematologic malignancies, have the potential to target acute myeloid leukemia through pathways that are distinct and complementary to current approaches. Here, we describe the development of a novel adoptive immunotherapy specific for this disease. We generated a second generation CD33-specific chimeric antigen receptor capable of redirecting cytolytic effector T cells against leukemic cells. CD33 is expressed in approximately 90% of acute myeloid leukemia cases and has demonstrated utility as a target of therapeutic antibodies. Chimeric antigen receptor-modified T cells efficiently killed leukemia cell lines and primary tumor cells in vitro. The anti-leukemia effect was CD33-specific, mediated through T-cell effector functions, and displayed tumor lysis at effector:target ratios as low as 1:20. Furthermore, the CD33-redirected T cells were effective in vivo, preventing the development of leukemia after prophylactic administration and delaying the progression of established disease in mice. These data provide pre-clinical validation of the effectiveness of a second-generation anti-CD33 chimeric antigen receptor therapy for acute myeloid leukemia, and support its continued development as a clinical therapeutic.