Recombinant interleukin-7 treatment of refractory Mycobacterium avium complex lung disease (IMPULSE-7): a pilot phase II, single-center, randomized, clinical trial

Abstract

Background: Nontuberculous mycobacteria disease is an emerging opportunistic infection that is often refractory to therapy. Interleukin 7 (IL-7) is a pleiotropic cytokine with broad-ranging effects that enhance immunity and augment monocyte/macrophage anti-Mycobacterium avium killing in vitro.

Objectives: This study evaluated IL-7 in patients with refractory Mycobacterium avium complex lung disease (MAC-LD).

Design: Prospective, single-center, randomized, study of IL-7 in patients with refractory MAC-LD.

Methods: Randomization (two sets of 4 weekly IL-7 injections) was stratified based on the presence of pulmonary cavities. The primary outcome was sputum culture conversion to negative within 6 months. Exploratory outcomes included investigation of potential molecular mechanisms of immunosuppression via single-cell RNA sequencing (scRNA-seq).

Results: Of the eight participants enrolled, six completed the IL-7 regimen, one completed one 4-week therapy, and one received a single dose of IL-7. All six participants who completed the regimen showed an increased absolute lymphocyte count (ALC), yet none converted their sputum culture to negative at 6 months. Similarly, there were no differences in secondary outcomes compared to baseline. IL-7 was well tolerated, and two participants showed an increase in time-positivity for MAC in their sputum culture. scRNA-seq revealed increased expression of genes involved in immunosuppressive pathways.

Conclusion: In adults with refractory MAC-LD, IL-7 did not result in sputum culture conversion. IL-7 reversed the underlying lymphopenia associated with MAC-LD and led to a sustained increase in ALC. The study was limited by a small sample size, and although a longer course of IL-7 combined with newer antimicrobials for may warrant further investigation, structural lung disease may be a stronger predictor of cure than immune dysfunction in MAC-LD.

Trial registration: The trial was registered in clinicaltrials.gov (NCT04154826).

Keywords: IL-7; NTM; nontuberculous mycobacteria; pulmonary disease; randomized clinical trial; refractory.

Figure 1.

Effect of IL-7 on sputum culture, sputum immunohistochemical staining, and ALCs in participants with refractory Mycobacterium avium complex lung infection. ALC counts are depicted for each patient over the course of the trial plus prior to trial initiation as available. IL-7 injections are denoted by vertical hashed lines and occurred at days 1, 8, 15, 21, 57, 64, 71, and 78. Blue lines indicate day 0, the day of the first IL-7 infection. Absolute lymphocyte counts were obtained from blood drawn within 1–3 h prior to the first injection of IL-7. Stars (*) indicate direct smear exam results, and placement corresponds to the numerical axis (study day). Days to culture growth indicated the number of days required before the culture became positive for MAC, and numbers corresponded to the dates when the samples for the cultures were collected from the participants. Participants under panel a were randomized to low-dose IL-7 (10 µg/kg/week) and those on panel b received high-dose IL-7 (20 µg/kg/week). ALC, absolute lymphocyte count; MAC, Mycobacterium avium complex.

Figure 2.

CD4+ Th cells from patients with MAC-LD have immunosuppressive signatures. (a) Uniform manifold approximation and projection (UMAP) plot of CD4+ T cells from MAC-LD patients at baseline (n = 3) and healthy controls (n = 15). The healthy control group consisted of 10 females and 5 males aged 49–74 years. Cells are colored according to the Seurat cluster to which they belong. Clusters were annotated manually based on marker features that passed statistical significance. Finally, inter-individual variation was minimized by running the “Harmony” algorithm, regressing donor differences as a variable. (b) Cells from (a) split by health status. (c) The bar graph represents the distribution of each cell type from (a) across health statuses. The discontinuous line crosses 50%, representing a hypothetical 50%–50% contribution. (d) Volcano plot of genes that were differentially expressed in MAC-LD CD4+ T cells versus in healthy. (e) Gene expression plots of marker genes of Treg cells in healthy (left) versus MAC-LD (right) cells. (f) Representative genes of Th1 cells in healthy (left) versus MAC-LD (right) cells. (g) Representative genes of KNCJ15 cells in healthy (left) versus MAC-LD (right) cells. In (e) to (g), gene names are represented on the right of the gene expression plot. MAC-LD, Mycobacterium avium complex lung disease.