A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract

Abstract

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651.

Graphical abstract

Figure 1.

Protocol schema. The rhIL-22 dimer F-652 was administered weekly for a total of 4 doses in combination with systemic corticosteroids to patients with newly diagnosed GI aGVHD. Patients were monitored for safety, drug PK, clinical endpoints including day-28 aGVHD response rates, and correlative analyses including fecal microbiota composition.

Figure 2.

PK and pharmacodynamics monitoring. (A) PK analyses showed detectable F-652 levels at 8 hours, 72 hours, and 7 days following the first and last doses of the rhIL-22 dimer. (B) Measurement of C-reactive protein (CRP) levels prior to administering F-652 and 3 days after administration. F-652 was administered on stay days 0 (dose 1), 7 (dose 2), 14 (dose 3), and 21 (dose 4). ∗P < .05, ∗∗P < .01.

Figure 3.

Treatment response. Per study design, 27 patients were enrolled with biopsy-proven lower GI aGVHD and monitored for their response to treatment with F-652 (rhIL-22) and systemic corticosteroids. The study was powered to indicate a promising treatment response if at least 60% of patients responded with an improvement in GVHD staging at day 28 after F-652 initiation. (A) The primary efficacy endpoint was achieved with an overall day-28 treatment response of 70%. (B) The majority of patients remained responders by day 56.

Figure 4.

GVHD biomarker–based stratification of study participants. Twenty-four patients in the study underwent GVHD risk assessment per the Mount Sinai Acute GVHD International Consortium scoring algorithm of plasma GVHD biomarkers REG3α and ST2. (A) Treatment response according to GVHD biomarker risk score at enrollment (n = 24). The majority of study participants had high or intermediate risk scores (n = 19); low-risk disease represented the minority of patients under study (n = 5.) Day-28 responses were observed in all risk groups. (B) Assessment of REG3α levels before and after F-652 treatment in 18 patients with paired plasma samples taken at study enrollment and again after completion of F-652 treatment. REG3α levels were significantly greater posttreatment when compared with baseline measurements. (C) Assessment of ST2 levels before and after F-652 treatment in 19 patients with paired plasma samples taken at study enrollment and again after completion of F-652 treatment. ST2 levels showed a mixed response posttreatment when compared with baseline measurements.

Figure 5.

Histology and PK profiles associated with treatment response. (A-B) Representative images of hematoxylin and eosin–stained histopathology performed at the onset of aGVHD and following rhIL-22 treatment with F-652 in a small subset of patients. (A) Pretreatment biopsy: colonic biopsy with crypt injury and extensive epithelial cell apoptosis. Arrows indicate apoptotic cells. (B) Day 28 posttreatment biopsy: colonic mucosa with only rare epithelial apoptotic bodies in basal crypts. Arrow points to a single apoptotic cell. (C) Drug PK levels 3 days and 7 days following the first dose of F-652 were greater in patients who went on to become treatment responders at day 28. (D) Drug PK levels 7 days following the first dose of F-652 were greater in patients who remained treatment responders at day 56. (E) Drug PK levels 7 days following the first dose of F-652 correlated with circulating plasma CCL20 concentrations after completion of F-652 treatment.

Figure 6.

Fecal microbiota analyses before and after treatment of lower GI aGVHD. (A) Overall microbiota composition in recipients of F-652 and corticosteroids (n = 22 patients) or corticosteroids alone (n = 27 patients). At baseline, microbial dysbiosis was present in all cohorts. Posttherapy, fecal samples from F-652 responders indicated an increased proportion of Lachnospiraceae. (B) PCA plots of microbial composition at baseline and following treatment. No distinct clusters can be found pretreatment in recipients of F-652 plus steroids or recipients of steroids alone. Samples clustering together in recipients of F-652 plus steroids following treatment are highlighted in the circle. (C) Comparison of β-diversity, focusing on PC2, prior to treatment and after GI GVHD treatment. (D) Abundance of Lachnospiraceae shown on the PCA plots of responders and nonresponders before and after GVHD treatment, highlighting enrichment of Lachnospiraceae in the previously identified cluster of F-652 responders. (E) Fold-change in Lachnospiraceae abundance following GVHD treatment, indicating Lachnospiraceae expansion in F-652 responders. (F) Fold-change in Blautia abundance following GVHD treatment, indicating Blautia expansion in F-652 responders. (G) Comparison of changes in Blautia abundance and overall microbial diversity indicates a correlation between the 2 parameters for GVHD patients responding to treatment with F-652 and steroids but not for patients treated with steroids alone.