IL7 Administration in Humans Results in Preferential Expansion of Naive and Memory CD4+ & CD8+ T Cells with a Relative Decrease in Regulatory T-Cells (T-Regs).

Abstract

Interleukin-7 (IL7) is a multifunctional cytokine with critical and non-redundant roles in T-cell development, T-lymphopoiesis and peripheral T-cell homeostasis. We report preliminary results of the first phase I study of recombinant human IL7, “CYT 99-007” (rhIL7). Adults with incurable malignancy (11 men and 3 women), 20–71 years old (median 48) received escalating doses (3, 10, 30 or 60 μg/kg/dose) subcutaneously every other day for 2 weeks.IL7 was overall well tolerated with no Maximum Tolerated Dose yet reached. Dose-dependent and age independent biological effects consistent with murine and non-human primate pre-clinical models were observed in all patients receiving 10 μg/Kg/dose or more: enlargement of spleen and lymph nodes (but not thymus) by CT scan and marked proliferation and expansion of T-cells subsets. Increases in CD4+ and CD8+ T-cells were most prominent in naïve T-cells (CD27+CD45RA+), including Recent Thymic Emigrants (RTE) (CD4+/CD45RA+/CD31+) with a mean 6-fold expansion, and in memory T-cells (CD27+CD45RA−) but less so in effector T-cells (CD27−). Furthermore, IL7 therapy resulted in a decline in the relative frequency of T-regs (50–80% decline in FoxP3 mRNA copies normalized to Actin mRNA copies in sorted CD4+ T-cells).Although the magnitude of biological effects was variable, the kinetics were similar in all T-cell subsets and at all effective doses. After one week of therapy at 30μg/ Kg /dose, 30–70% of naïve CD4+ and CD8+ T-cells were in cycle (Ki-67+) and expressed elevated levels of Bcl-2. Bcl-2 up-regulation (maintained at week 2) and high proliferation rates resulted in T-cell expansion (mean of 6- and up to 14-fold in some individuals at the 30μg dose) persisting one to several weeks after treatment. Consistent with animal data, we observed IL7 receptor α-chain (IL7Rα) down-regulation: both IL7Rα mean fluorescent intensity by flow cytometry (CD127) and mRNA copy numbers declined more than 50% at one week. By the end of treatment, proliferation rates were halved and down to baseline by week 3, coincident with recovery of IL7Rα expression after cessation of treatment. The T-cell increase was primarily due to IL7 induced peripheral expansion. There was no dilution effect of T-Cell Receptor Excision Circles (TREC) numbers per 105 CD4+ sorted cells which suggests cell recruitment or expansion, consistent with preclinical data but does not exclude a thymic contribution.rhIL7 is safe at biologically active doses in humans and induces an expansion of naïve (including RTE) and memory T-cells. In contrast to IL2, IL7's role in T-regs homeostasis appears to be minimal. rhIL7 may prove clinically valuable in adoptive immunotherapy as an immuno-restorative agent in conditions of disease (HIV) or chemotherapy induced T-cell depletion or as an adjunct to tumor vaccination for immune response modulation.