Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy

Abstract

Purpose: Interleukin-7 (IL-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 (immunosenescence), pathologic (HIV), or iatrogenic (postchemotherapy and posthematopoietic stem cell transplant), and may have roles in immune reconstitution or enhancement of immunotherapy. We report here on the toxicity and biological activity of recombinant human IL-7 (rhIL-7) in humans.

Design: Subjects with incurable malignancy received rhIL-7 subcutaneously every other day for 2 weeks in a phase I interpatient dose escalation study (3, 10, 30, and 60 microg/kg/dose). The objectives were safety and dose-limiting toxicity determination, identification of a range of biologically active doses, and characterization of biological and, possibly, antitumor effects.

Results: Mild to moderate constitutional symptoms, reversible spleen and lymph node enlargement, and marked increase in peripheral CD3(+), CD4(+), and CD8(+) lymphocytes were seen in a dose-dependent and age-independent manner in all subjects receiving >or=10 microg/kg/dose, resulting in a rejuvenated circulating T-cell profile, resembling that seen earlier in life. In some subjects, rhIL-7 induced in the bone marrow a marked, transient polyclonal proliferation of pre-B cells showing a spectrum of maturation as well as an increase in circulating transitional B cells.

Conclusion: This study shows the potent biological activity of rhIL-7 in humans over a well-tolerated dose range and allows further exploration of its possible therapeutic applications.

Figure 1. Clinical parameter kinetics with rhIL-7 therapy

Cohorts: 1, black; 2, green: 3, red: 4, blue a)Top left: ALC cohort mean ± SEM. Others: mean + SEM for all subjects. b) Left: mean spleen size; spleen on CT: baseline, day 14, 2 months. c) Left: mean absolute numbers mature B cells; right: immature B cells, mean percentage of CD19+ population.

Figure 2

H&E, immunostaining (CD10, Tdt) (200X) and giemsa stain (400X), pre and post rhIL-7 therapy, in subject with marked marrow expansion (UPN08)

Figure 3. Bone Marrow B cell

a) CD19⁺ cells and subsets: % total BMMC. (subjects < 30 years in red). Dxx; 4-10 weeks; correlation between BM CD19+/CD10+ pre-B cells and PB increases in: CD20⁺ (●); CD19⁺/D10⁺ (○). b) Flow cytometry scatterplots of marrow early B cell precursors in subject with marked expansion (UPN08) illustrating progressive maturation Panel A. Bone marrow cells- ungated data, x-axis CD45 PerCP, y-axis CD19 APC, CD19 positive B cells (in polygonal analysis gate) have increasing levels of CD45 and CD19 expression consistent with ongoing maturation. Panel B. CD19 positive B cells (gate-polygonal gate in A), x-axis CD20 FITC, y-axis CD10 PE, CD19 positive B cells have increasing levels of CD20 expression and decreasing levels of CD10 expression consistent with ongoing maturation. Panel C. CD19 positive B cells (gate-polygonal gate in A), x-axis CD45 PerCP, y-axis CD34 PE, CD19 positive B cells have increasing levels of CD45 expression and decreasing levels of CD34 expression consistent with ongoing maturation.