title: B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells.
abstract: We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients. Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFNγ and TNF. The severity of acute toxicities experienced by the patients correlated with serum IFNγ and TNF levels. The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFNγ ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions. Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+) cells in vivo; however, reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions.
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI), Bethesda, MD 20892, USA. kochendj@mail.nih.gov
authors.forename: James N
authors.initials: JN
authors.lastname: Kochenderfer
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: David E
authors.initials: DE
authors.lastname: Spaner
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.forename: Giao Q
authors.initials: GQ
authors.lastname: Phan
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sherry
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
authors.forename: Laura
authors.initials: L
authors.lastname: Devillier
authors.forename: Robert
authors.initials: R
authors.lastname: Carpenter
authors.forename: Debbie-Ann N
authors.initials: DA
authors.lastname: Nathan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Carolyn
authors.initials: C
authors.lastname: Laurencot
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D018941:Antigens, CD19 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000009:adverse effects* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D012074:Remission Induction; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014161:Transduction, Genetic
chemical_list: D018941:Antigens, CD19; D016207:Cytokines; D011993:Recombinant Fusion Proteins