In this issue of Blood, Ponce et al1 report the results of a multicenter single-arm, phase 2 study evaluating the safety and efficacy of F-652, a novel recombinant human interleukin-22 (IL-22) dimer used in combination with systemic corticosteroids for treatment of newly diagnosed gastrointestinal (GI) acute graft-versus-host disease (GVHD). There was no dose-limiting toxicity, and the prespecified primary endpoint, response at day 28, was achieved by 19 of 27 patients (70%; 80% confidence interval, 56% to 79%).
Despite improvement in acute GVHD prophylaxis and treatment, GVHD remains the leading cause of early morbidity and mortality, apart from relapse, after allogeneic hematopoietic stem cell transplantation (alloHCT).2 In particular, lower GI acute GVHD is associated with an increased risk of nonrelapse mortality.2 Systemic corticosteroids are the standard first-line treatment for acute GVHD, with a low response rate, approximately 50%. Furthermore, although approval of ruxolitinib for steroid-refractory acute GVHD was a significant improvement for patients with this disease, no progress has been made regarding first-line treatment. In fact, several phase 3 randomized studies, which evaluated the adjunction of another immunosuppressive drug to corticosteroids to improve acute GVHD response rate at day 28, were all negative.3 Therefore, innovative strategies, preferably steroid sparing, are needed to improve response.
During GI acute GVHD, all mature gut epithelial cells, including enterocytes, Paneth, goblet, tuft, and enteroendocrine cells, are targeted. This leads to alteration of the tissue microenvironment, disruption of tissue homeostasis, and amplification of GVHD-induced tissue damage. In addition, during GI acute GVHD, activated T cells also directly target intestinal stem cells in an interferon gamma–dependent manner.4 In the homeostatic state, intestinal stem cells produce approximatively 10 offspring per hour in each crypt, which then migrate to the villus. Therefore, during GI acute GVHD, depletion of cycling intestinal stem cells in the crypt soon leads to villus atrophy, resulting in refractory colitis.
Importantly, intestinal stem cells and their downstream progenitors express Il-22 receptors, and IL-22 increases proliferation and promotes intestinal stem cell expansion.5 In the alloHCT setting, the conditioning regimen leads to an increased production of intestinal IL-22 by IL-23–responsive innate lymphoid cells from the transplanted recipient.6 Nevertheless, during GI acute GVHD, innate lymphoid cell frequency and IL-22 amounts are decreased, leading to increased crypt apoptosis, depletion of intestinal stem cells, and loss of epithelial integrity.6 Lindemans et al demonstrated in a murine model that treatment with IL-22 in vivo after murine alloHCT enhanced recovery of intestinal stem cells, increased epithelial regeneration, and reduced intestinal pathology and mortality from GVHD.5
Based on these preclinical data, Ponce et al evaluated the use of the recombinant human IL-22 dimer, F-652, in GI acute GVHD in a phase 2 prospective study published in this issue of Blood. Importantly, F-652 was proven to be safe, xerosis and xerophthalmia being the most common attributable side effects. Of note, IL-22 can have a pathogenic role in chronic inflammatory diseases such as psoriasis.7 Moreover, we have previously reported that donor T-cell–derived IL-22 can exacerbate the inflammation in the GI tract and contribute to the severity of acute GVHD.8 Nevertheless, no significant increases in inflammatory cytokine levels were observed after F-652 treatment. Furthermore, the current data suggest that higher concentrations of F-652 translate into improved GVHD response rates.
In addition to its effect on intestinal stem cell proliferation and expansion, IL-22 also induces epithelial production of innate antimicrobial peptides. Therefore, given the relationship between the GI microbiome and acute GVHD outcomes,9 Ponce et al investigated fecal microbiota composition before and after F-652 treatment. They found that although at baseline all patients exhibited microbiome dysbiosis, after treatment with F-652 and steroids, responders exhibited a distinct fecal microbiota composition associated with an expansion of Lachnospiraceae, including an increase in the genus Blautia. Importantly, among a cohort treated with steroids in the absence of F-652 in a retrospective historical control cohort of GI acute GVHD, there was not a similar microbial shift in responding patients. Overall, this suggests that F-652 can contribute to correction of gut microbiota dysbiosis in the setting of GI acute GVHD. These results offer a strong opportunity for development of a synergistic approach in the combination of fecal microbiota transplantation and F-652 for treatment of GI acute GVHD.10
Finally, despite including only patients with GI acute GVHD, a group particularly prone to treatment failure, this study reports an overall response rate of 70% at day 28, comparable to those of 74% and 66% reported respectively with corticosteroid plus itacitinib and corticosteroid plus placebo in the randomized phase 3 GRAVITAS-301 study, which included only 42% of patients with lower GI acute GVHD.3 This further confirms that F-652 deserves evaluation in a phase 3 randomized clinical trial and that it can likely be a key player in combination with new gut microbiota manipulation approaches, in particular fecal microbiota transplantation, within the next decade.10
Conflict-of-interest disclosure: F.M. reports honoraria from Therakos/Mallinckrodt, Janssen, Biocodex, Sanofi, Jazz Pharmaceuticals, Gilead, Novartis, BMS-Celgene, and Astellas, all outside the scope of this work. M.M. reports grants, lecture honoraria, and research support from Adaptive Biotechnologies, Amgen, Astellas, BMS-Celgene, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, Takeda, and Sanofi, all outside the scope of this work.