Journal Article

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia

Morrissette, J J D, June, C H, Porter, D L, Song, D, Gill, S, Carroll, M, Shestova, O, Kenderian, S S, Aikawa, V, Klichinsky, M, Ruella, M, Scholler, J

2015

Overview

Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/107 / 13/109 / 13/21 / 13/31 / 13/44 / 13/51 / 38/32 / 38/5 / 631/250/1619/554/1775 / 64/110 / 64/60 / 692/308/2778 / 692/699/67/1059/602 / 692/699/67/1990/283/1897 / Acute myeloid leukemia / Animals / Antigen receptors, T cell / Antigens / Blast Crisis - immunology / Blast Crisis - metabolism / Blast Crisis - pathology / Blast Crisis - therapy / Blotting, Western / Cancer Research / CD19 antigen / Cell Proliferation / Cell receptors / Cell therapy / Cell- and Tissue-Based Therapy / Cellular therapy / Chimeric antigen receptors / Critical Care Medicine / Effector cells / Electroporation / Female / Flow Cytometry / Gemtuzumab ozogamicin / Gene expression / Gene transfer / Genetic aspects / Health aspects / Hematology / Hemopoiesis / Humans / Immunoenzyme Techniques / Immunotherapy / Intensive / Internal Medicine / Leukemia / Leukemia, Myeloid, Acute - immunology / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / Leukemia, Myeloid, Acute - therapy / Lymphocytes / Lymphocytes T / Medical prognosis / Medicine / Medicine & Public Health / Methods / Mice / Mice, Inbred NOD / Mice, SCID / Mice, Transgenic / Monoclonal antibodies / mRNA / Myelodysplastic Syndromes - immunology / Myelodysplastic Syndromes - metabolism / Myelodysplastic Syndromes - pathology / Myelodysplastic Syndromes - therapy / Myeloid leukemia / Myelosuppression / Oncology / original-article / Patient outcomes / Real-Time Polymerase Chain Reaction / Receptors / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Reverse Transcriptase Polymerase Chain Reaction / RNA modification / RNA, Messenger - genetics / Sialic Acid Binding Ig-like Lectin 3 - immunology / Sialic Acid Binding Ig-like Lectin 3 - metabolism / T cells / Therapy / Toxicity / Toxicity testing / Transplantation / Tumor Cells, Cultured / Viability / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation