Transfer of influenza vaccine-primed costimulated autologous T cells after stem cell transplantation for multiple myeloma leads to reconstitution of influenza immunity: results of a randomized clinical trial

Abstract

Severe immune deficiency follows autologous stem cell transplantation for multiple myeloma and is associated with significant infectious morbidity. This study was designed to evaluate the utility of a pretransplantation vaccine and infusion of a primed autologous T-cell product in stimulating specific immunity to influenza. Twenty-one patients with multiple myeloma were enrolled from 2007 to 2009. Patients were randomly assigned to receive an influenza-primed autologous T-cell product or a nonspecifically primed autologous T-cell product. The study endpoint was the development of hemagglutination inhibition titers to the strain-specific serotypes in the influenza vaccine. Enzyme-linked immunospot assays were performed to confirm the development of influenza-specific B-cell and T-cell immunity. Patients who received the influenza-primed autologous T-cell product were significantly more likely to seroconvert in response to the influenza vaccine (P = .001). Seroconversion was accompanied by a significant B-cell response. No differences were observed in the global quantitative recovery of T-cell and B-cell subsets or in global T-cell and B-cell function. The provision of a primed autologous T-cell product significantly improved subsequent influenza vaccine responses. This trial was registered at www.clinicaltrials.gov as #NCT00499577.

Figures

Figure 1

The study protocol. (A) The clinical protocol is shown schematically. Primed patients received a vaccine both before and after ASCT (V-T-V), whereas the nonprimed group received the vaccine only after ASCT (T-V). (B) The CONSORT diagram of the study enrollment.

Figure 2

Influenza titers. HAI influenza titers are induced to high levels in the primed group. Geometric mean titers and 5%-95% confidence intervals are displayed. The mixed effects model for repeated measures showed P = .006 for H1N1 and P < .0001 for H3N2.

Figure 3

B cells are depleted after melphalan conditioning. Plotted are the average absolute B-cell counts (top), absolute numbers of naive B cells (IgM+, CD27−; middle), or percentage of B cells with a switched memory phenotype (IgM−, CD27+; bottom) as a function of time. At most time points, most of the B cells are naive B cells. During the time of maximal B-cell depletion (day 14), switch memory B cells predominate.

Figure 4

Effect of melphalan and T-cell infusion of T-cell subsets. T-cell subsets are differentially affected by conditioning and autologous T-cell infusions. The subsets were identified as described in “Immunologic assays,” and the fraction of each subset within the CD3 population is plotted on the y-axis.

Figure 5

Functional analysis of T-cell and B-cell responses. Functional responses to antigen are augmented in the primed group. T-cell and B-cell responses to influenza antigens were measured by antigen-specific ELISPOTS. CD4 T-cell antigen–specific responses (γ-interferon responses to intact protein after CD8 T-cell depletion) were increased in the primed group compared with the nonprimed group at the T-cell harvest time point (P = .02). There were no statistically significant differences between the 2 groups for the CD8-specific responses (responses to influenza peptides), and the global responses (phorbol myristate acetate [PMA] and ionomycin and total IgG) also did not differ between the 2 groups at any time point.