title: CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.
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.
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Marco L
authors.initials: ML
authors.lastname: Davila
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Kloss
authors.forename: Gertrude
authors.initials: G
authors.lastname: Gunset
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D019070:Cell Lineage / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007121:Immunocompetence; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008212:Lymphocyte Depletion; D051379:Mice; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D012074:Remission Induction / Q000379:methods; D014161:Transduction, Genetic
chemical_list: D018941:Antigens, CD19; D018906:Antineoplastic Agents, Alkylating; D018106:CD28 Antigens; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D050506:Mutant Chimeric Proteins; D011948:Receptors, Antigen, T-Cell; D003520:Cyclophosphamide