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Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T cell therapy

Vijay G. Bhoj, Dimitrios Arhontoulis, Gerald Wertheim, James Capobianchi, Colleen A. Callahan, Christoph T. Ellebrecht, Amrom E. Obstfeld, Simon F. Lacey, Jan J. Melenhorst, Farzana Nazimuddin, Wei-Ting Hwang, Shannon L. Maude, Mariusz A. Wasik, Adam Bagg, Stephen Schuster, Michael D. Feldman, David L. Porter, Stephen A. Grupp, Carl H. June and Michael C. Milone

Key points

  • CD19-targeted T cell immunotherapy reveals that a population of plasma cells lacking CD19 expression survives long-term, independent of B cells.

  • Pre-existing humoral immunity to vaccine-related antigens can persist in patients despite marked B-cell aplasia following CTL019 immunotherapy.

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 (CAR)-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 were 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 IgG and IgA titers remain relatively stable for at least 6 and 12 months post treatment, 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.

  • Submitted January 22, 2016.
  • Accepted April 29, 2016.