title: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.
abstract: Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials. We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non-cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months. Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR(+) T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex-independent approach for the effective treatment of B cell malignancies.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.forename: Sharyn
authors.initials: S
authors.lastname: Katz
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Adam
authors.initials: A
authors.lastname: Bagg
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000368:Aged; D000941:Antigens / Q000276:immunology*; D018941:Antigens, CD19 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007938:Leukemia / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D011971:Receptors, Immunologic / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000276:immunology
chemical_list: D000941:Antigens; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D016207:Cytokines; D011971:Receptors, Immunologic