Perspective on potential clinical applications of recombinant human interleukin-7

Abstract

Interleukin-7 has critical and nonredundant roles in T cell development, hematopoiesis, and postdevelopmental immune functions as a prototypic homeostatic cytokine. Based on a large body of preclinical evidence, it may have multiple therapeutic applications in immunodeficiency states, either physiologic (immuno-senescence), pathologic (HIV) or iatrogenic (postchemotherapy and posthematopoietic stem cell transplant) and may have roles in immune reconstitution or enhancement of immunotherapy. Early clinical development trials in humans show that, within a short time, rhIL-7 administration results in a marked preferential expansion of both naive and memory CD4 and CD8 T cell pools with a tendency toward enhanced CD8 expansion. As a result, lymphopenic or normal older hosts develop an expanded circulating T cell pool with a profile that resembles that seen earlier in life with increased T cell repertoire diversity. These results, along with a favorable toxicity profile, open a wide perspective of potential future clinical applications.

Figure 1.

Effects of rhIL-7 Therapy on Circulating lymphocytes and Spleen Size. RhIL-7 injections indicated by tick marks on X-axis along with baseline, days 7, 14, 21, and 28 data points (additional data points are shown for total lymphocytes count only: day 1 for all and day 55–90 for subjects treated with 30 or 60 μg/kg/d). Mean value for each cohort (± SEM) are plotted: 3 μg/kg/d (black); 10 μg/kg/d (green); 30 μg/kg/d (red); 60 μg/kg/d (blue). (A) Absolute lymphocyte count from complete blood counts (left panels) and percent change in absolute numbers over baseline (right panels) for CD3⁺/CD4⁺ and CD3⁺/CD8⁺ cells the respective subsets are shown. (B) Spleen size: percent changes from the pretherapy bidimensional product by CT scan. (C, D, and E) CD3⁺/CD4⁺ (left panels) and CD3⁺/CD8⁺ subsets (right panels). (C) “Ki-67”: percentage of cells expressing Ki-67 (flow cytometry). (D) “IL-7Rα” expression as mean fluorescence intensity via flow cytometry. (E) “bcl-2” expression as mean fluorescence intensity (after subtracting background staining for each subset) via flow cytometry.

Figure 2.

RhIL-7 induces preferential expansion of Naive T cells and CD4⁺ Memory T Cells (with cycling and bcl-2 expression increase across subsets). Subjects treated at 3 μg/kg/d (white), 10 μg/kg/d (speckled), 30 μg/kg/d (grey) and 60 μg/kg/d (black). The time points shown represent the point of maximal increase for each parameter: (A) Percent increase in absolute circulating cell number (/mm³) over pretherapy value for each subset at Day 21 following rhIL-7. (B) Net increase from baseline in the proportion of Ki67⁺ cells in each subset at day 7 of rhIL-7 therapy. (C) Net increase in bcl-2 mean fluorescence intensity in each subset at day 14. (D) Net increase in cell number at day 21 in subsets defined by CCR7 and CD45RA surface expression as follows: Naive (CCR7⁺CD45RA⁺), central memory (CCR7⁺CD45RA⁻), effector memory (CCR7⁻CD45RA⁻), and effector RA (CCR7⁻CD45RA⁺).