Abstract
Although many adults with B cell acute lymphoblastic leukemia (B-ALL) are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs) and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ζ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, CD19 / genetics
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Antigens, CD19 / immunology*
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Antineoplastic Agents, Alkylating / pharmacology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology*
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B-Lymphocytes / pathology
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CD28 Antigens / genetics
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CD28 Antigens / immunology
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CD3 Complex / genetics
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CD3 Complex / immunology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / transplantation
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Cell Lineage / immunology
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Cyclophosphamide / pharmacology
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Disease Models, Animal
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Humans
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Immunocompetence
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Immunophenotyping
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Immunotherapy, Adoptive / methods*
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Lymphocyte Depletion
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Mice
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Mutant Chimeric Proteins / genetics
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Mutant Chimeric Proteins / immunology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy*
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology*
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Remission Induction / methods
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Transduction, Genetic
Substances
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Antigens, CD19
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Antineoplastic Agents, Alkylating
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CD28 Antigens
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CD3 Complex
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CD3 antigen, zeta chain
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Mutant Chimeric Proteins
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Receptors, Antigen, T-Cell
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Cyclophosphamide