Abstract
To develop a therapy for drug-resistant B-lineage acute lymphoblastic leukemia (ALL), we transduced T lymphocytes with anti-CD19 chimeric receptors, consisting of an anti-CD19 single-chain variable domain (reactive with most ALL cases), the hinge and transmembrane domains of CD8alpha, and the signaling domain of CD3zeta. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-zeta') containing the signaling domain of 4-1BB (CD137; a crucial molecule for T-cell antitumor activity) to that of a receptor lacking costimulatory molecules. Retroviral transduction produced efficient and durable receptor expression in human T cells. Lymphocytes expressing anti-CD19-BB-zeta receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB-zeta lymphocytes were remarkably effective in cocultures with bone marrow mesenchymal cells, and against leukemic cells from patients with drug-resistant ALL: as few as 1% anti-CD19-BB-zeta-transduced T cells eliminated most ALL cells within 5 days. These cells also expanded and produced interleukin-2 in response to ALL cells at much higher rates than those of lymphocytes expressing equivalent receptors lacking 4-1BB. We conclude that anti-CD19 chimeric receptors containing 4-1BB are a powerful new tool for T-cell therapy of B-lineage ALL and other CD19+ B-lymphoid malignancies.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Antigens, CD
-
Antigens, CD19 / immunology
-
Burkitt Lymphoma / pathology
-
Burkitt Lymphoma / therapy*
-
CD3 Complex / chemistry
-
CD3 Complex / genetics
-
CD3 Complex / pharmacology
-
CD8 Antigens / chemistry
-
CD8 Antigens / genetics
-
CD8 Antigens / pharmacology
-
Cell Line, Tumor
-
Coculture Techniques
-
Cytotoxicity Tests, Immunologic
-
Humans
-
Immunoconjugates / genetics
-
Immunoconjugates / pharmacology
-
Immunoglobulin Variable Region / genetics
-
Immunoglobulin Variable Region / pharmacology
-
Immunotherapy
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
-
Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy*
-
Protein Structure, Tertiary
-
Receptors, Nerve Growth Factor / genetics
-
Receptors, Nerve Growth Factor / therapeutic use*
-
Receptors, Tumor Necrosis Factor / genetics
-
Receptors, Tumor Necrosis Factor / therapeutic use*
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / pharmacology*
-
T-Lymphocytes / cytology
-
T-Lymphocytes / immunology
-
T-Lymphocytes / metabolism
-
Transduction, Genetic
-
Tumor Necrosis Factor Receptor Superfamily, Member 9
Substances
-
Antigens, CD
-
Antigens, CD19
-
CD3 Complex
-
CD3 antigen, zeta chain
-
CD8 Antigens
-
Immunoconjugates
-
Immunoglobulin Variable Region
-
Receptors, Nerve Growth Factor
-
Receptors, Tumor Necrosis Factor
-
Recombinant Fusion Proteins
-
TNFRSF9 protein, human
-
Tumor Necrosis Factor Receptor Superfamily, Member 9