title: Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy.
abstract: The mechanisms underlying the maintenance of long-lasting humoral immunity are not well understood. Studies in mice indicate that plasma cells (PCs) can survive up to a lifetime, even in the absence of regeneration by B cells, implying the presence of long-lived PCs as a mechanism for long-lasting immunity. Evidence from humans treated with anti-CD20, which depletes circulating B cells, also suggests B-cell-independent long-term survival of some PCs. On the other hand, antibody responses may be sustained solely by short-lived PCs with repopulation from clonally related memory B cells. To explore PC longevity and humoral immunity in humans, we investigated the fate of PCs and their antibodies in adult and pediatric patients who received chimeric antigen receptor-based adoptive T-cell immunotherapy targeting CD19 to treat B-cell lineage malignancies (CTL019). Treatment with CTL019 is frequently associated with B-cell aplasia that can persist for years. Serum antibody titers to vaccine-related antigens were measured, and quantitative assessment of B cells and PCs in blood and bone marrow was performed at various time points before and after CTL019 therapy. While total serum immunoglobulin concentrations decline following CTL019-induced B-cell aplasia, several vaccine/pathogen-specific serum immunoglobulin G and A (IgG and IgA) titers remain relatively stable for at least 6 and 12 months posttreatment, respectively. Analysis of bone marrow biopsies after CTL019 revealed 8 patients with persistence of antibody-secreting PCs at least 25 months post-CTL019 infusion despite absence of CD19(+)CD20(+) B cells. These results provide strong evidence for the existence of memory B-cell-independent, long-lived PCs in humans that contribute to long-lasting humoral immunity.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Vijay G
authors.identifier: 0000-0003-2857-4092
authors.initials: VG
authors.lastname: Bhoj
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Arhontoulis
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Gerald
authors.initials: G
authors.lastname: Wertheim
authors.affiliation: Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: James
authors.initials: J
authors.lastname: Capobianchi
authors.affiliation: Division of Bone Marrow Transplantation, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Callahan
authors.affiliation: Department of Dermatology and.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Ellebrecht
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Amrom E
authors.initials: AE
authors.lastname: Obstfeld
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Melenhorst
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Farzana
authors.initials: F
authors.lastname: Nazimuddin
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.affiliation: Division of Bone Marrow Transplantation, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Maude
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Mariusz A
authors.identifier: 0000-0002-1988-3670
authors.initials: MA
authors.lastname: Wasik
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Adam
authors.initials: A
authors.lastname: Bagg
authors.affiliation: Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Stephen
authors.initials: S
authors.lastname: Schuster
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Division of Bone Marrow Transplantation, Children's Hospital of Philadelphia, Philadelphia, PA; and.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
authors.forename: Michael C
authors.identifier: 0000-0002-1580-9844
authors.initials: MC
authors.lastname: Milone
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D018941:Antigens, CD19 / Q000097:blood / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002648:Child; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation
chemical_list: D018941:Antigens, CD19; C000604811:CD19 molecule, human; D007070:Immunoglobulin A; D007074:Immunoglobulin G