Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation

Abstract

Delays in immune recovery after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with increased risks of infection and relapse. IL-7 has a central role in T-cell development and survival and enhances immune recovery in murine models of allo-HSCT. We performed a phase 1 trial of r-hIL-7 (CYT107) in recipients of T-cell depleted allo-HSCTs. Twelve patients were treated with escalating doses of r-hIL-7 administered weekly for 3 weeks. The study drug was well tolerated with only one patient developing acute skin GVHD. At baseline, patients were profoundly lymphopenic. CYT107 induced a doubling in CD4(+) and CD8(+) T cells. The main effect of IL-7 was an expansion of effector memory T cells, the predominant subset identified in our patients. There was no significant effect on CD4(+)CD25(+)FoxP3(+) T cells, NK, or B cells. Importantly, we not only saw quantitative increases in T cells after a short course of IL-7 but also demonstrated an increase in functional T cells, including viral-specific T cells that recognize CMV. Enhanced TCR diversity was also observed after treatment. Our results indicate that r-hIL-7 can enhance immune recovery after a T cell-depleted allo-HSCT without causing significant GVHD or other serious toxicity (www.clinicaltrials.gov; NCT00684008).

Figures

Figure 1

Pharmacokinetic studies demonstrate rapid plasma clearance of IL-7 after injection of CYT107. (A) Individual patients at 3 dose levels. (B) Data are mean ± SEM for each dose level.

Figure 2

CYT107 induces increases in T cells in the peripheral blood but does not affect NK cells or B cells. (A) Absolute CD3 counts. (B) Ratio CD3 count/baseline. (C) Absolute CD4 counts. (D) Ratio CD4 count/baseline. (E) Absolute CD8 counts. (F) Ratio CD8 count/baseline. (G) Absolute B-cell counts. (H) Ratio B-cell count/baseline. (I) Absolute NK-cell counts. (J) Ratio NK count/baseline. Absolute counts are shown for individual patients. The ratios (mean ± SEM) are shown for each cohort and are calculated using as a baseline value the mean of the pretreatment and day 0 values. The shaded area represents the CYT107 treatment interval (injections were given once a week as described in “Results”). (A,C,E,G,I) The horizontal line indicates the lower limit of normal.

Figure 3

CYT107 induces the expansion of effector memory CD4+ and CD8+ T cells but no changes in Treg or CD127 expression. (A) CYT107 predominantly induces an expansion of effector memory T cells with an increase in naive CD4+ and CD8+ T cells in a minority of patients. Each panel represents absolute values of T-cell subsets of CD4+ or CD8+ T cells using CD45RA and CCR7 expression to distinguish naive (CD45RA+CCR7+), central memory (CD45RA−CCR7+), effector memory (CD45RA−CCR7−), and effector (CD45RA+CCR7−) T cells. Data for individual patients are shown. (B) CYT107 administration does not affect the relative frequency of Tregs, defined as CD4+CD25hiFoxP3+ T cells. Left: Absolute Treg counts for individual patients. Right: Mean ratio Treg count/baseline ± SEM for each cohort. (C) CYT107 administration does not affect long-term expression of CD127 on CD4+ or CD8+ T cells (data for individual patients shown).

Figure 4

CYT107 did not have a significant effect on thymic output in most patients. (A) Absolute CD4+ and CD8+ RTE counts, identified by the CD4+CD45RA+CD31+CD62Lbright CD95dim and CD8+CD103+CD62LbrightCD95dim phenotypes for individual patients. (B) CD4+ and CD8+ TRECs are shown for individual patients in each cohort.

Figure 5

Administration of CYT107 enhances functional T-cell responses. (A) Reponses to PHA for individual patients. The horizontal line indicates the lower limit of normal. (B) Rapid increase in CMV-specific responses in patient 14-206 determined by A0201-restricted pp65 immunodominant peptide NLVPMVATV (NLV) tetramer.

Figure 6

Administration of CYT107 enhances TCR diversity. (A) Evolution of the mean combinatorial diversity (hTRβ) over time. Individual patients and the mean diversity are shown. The shaded area on each graph represents the CYT107 treatment interval. For patient 14-303, only the last study time point was available for analysis because of profound lymphopenia before that sample. (B) Relationship over time between T-cell counts and hTRβ (NDL representation). Most patients shift from NDL1 (low CD3/low diversity) toward NDL2 (low CD3/normal diversity) after treatment with CYT107. Individual patients are shown. Squares, circles, and triangles represent patients in the 10-, 20-, and 30-μg/kg cohorts, respectively. (C) The image represents a 3D graph of immune combinatorial diversity at each studied time point (pre, D0, D28, D77) after treatment with CYT107 in representative patient 14-207. Each peak represents the rearrangement between a V gene family and a J segment. V families are represented on the x-axis. J segments are represented on the y-axis. The intensity of these rearrangements is represented on the z-axis, varying between 0 and 5.

Figure 7

Evolution over time of the major hTRB VJ rearrangements identified per patient. Only patient 14-205 has no major rearrangement detected. The sample at D-7 was not available for patient 14-206, and for patient 14-303 only data for D77 were available. Each color represents a major hTRβ VJ rearrangement. The red dotted line indicates the average for each patient.