Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease

Abstract

• Low-dose IL-2 is efficacious in steroid-refractory cGVHD, with objective responses in .50% of patients, and durable disease control.• IL-2 initiation earlier after cGVHD onset, prior to severe impairment of Treg:Tcon ratios, improves likelihood of clinical response.Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4 1 CD25 1 FOXP3 1 regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2 (1 3 10 6 IU/m 2 ) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rose >fivefold (P < .001) and >fourfold (P < .001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg:Tcon ratio rose >fivefold (P < .001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P 5 .005; 249 vs 461 days after cGVHD onset; P 5 .03). Treg:Tcon ratios ‡0.07 at baseline and ‡0.2 at week 1 also predicted clinical response (P 5 .003; P 5 .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg:Tcon ratio gradually normalized. Lowdose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated. (Blood. 2016;128(1):130-137)

An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition

“…Relevant to cGvHD in patients, we previously showed that patients developing cGvHD presented altered Treg homeostasis with quantitative deficiency (5). Strategies to expand Tregs in vivo were efficient at reducing but not uniformly eliminating disease severity (10). Similarly, we observed abnormal homeostasis and chronically activated B cells (6,11), offering the possibility to deplete or target them (12)(13)(14).…”

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

“…Koreth et al reported that low-dose IL-2 could effectively improve the symptoms of cGVHD. 14,16 Therefore, treatment with IL-2 plays not only a therapeutic role but also a prophylactic role on cGVHD. Previous studies explored the roles of Treg cells in cGVHD that were mainly obtained from the patient's sample after the diagnosis of cGVHD.…”

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

“…136,153 Given the failure of Tregs during cGVHD and the challenges of generating sufficient Tregs for adoptive transfer to treat cGVHD patients, restorative approaches to date have focused on low-dose IL-2 administration to expand Tregs in vivo with ;50% of patients showing Treg expansion and some clinical response as long as therapy is continued. 154,155 Recently, the adoptive transfer of Tregs with or without IL-2 and/or rapamycin has begun to be tested in clinical trials in an effort to increase the proportion and depth of patient response.…”