LOW DOSE IL-2 FOR THE TREATMENT OF MODERATE TO SEVERE ULCERATIVE COLITIS

Abstract

Abstract Background A significant proportion of patients with ulcerative colitis (UC) have suboptimal responses to medical therapy. Expansion of regulatory T cells (Tregs), but not conventional T cells (Tcons), through the use of low doses (LD) of the T cell growth factor Interleukin-2 (IL-2, Proleukin®), has been a promising approach in other immune-mediated diseases and pre-clinical humanized UC mouse models. We performed a phase 1b/2a clinical trial in patients with moderate-to-severe UC to determine if subcutaneously (SC) administered LD IL-2 is safe and results in a biological response. Methods An open-label single arm phase 1b/2a trial of LD SC IL-2 in moderate-to-severe UC patients involving 2 phases: (1) dose escalation phase, in which three sequentially increasing dose levels were tested: 0.3x106 IU/m2/day (Dose A), 1x106 IU/m2/day (Dose B) or 1.5x106 IU/m2/day (Dose C); (2) treatment at the maximum tolerated dose (MTD) phase, defined as the highest tolerated dose level at which fewer than 2 evaluable subjects experienced a dose limiting toxicity (DLT). Adult patients with UC and a Mayo score of 6–12 were included and received a daily SC injection. The primary objectives were safety and determination of MTD. Clinical and laboratory assessments occurred pre-treatment and at weeks 1, 2, 4, 6, 8 and 12, with sigmoidoscopy at baseline and week 8. Peripheral Treg (pTreg) expansion was defined as >2X increase in % CD4+CD25+ cells. Tcon activation is measured by pSTAT5 in CD4+CD25- cells. Results 26 patients were enrolled. Baseline characteristics were similar among groups. There were no serious adverse events (AEs). Common (occuring in >10% of patients) AEs included injection site reactions and malaise across all doses. In the dose escalation phase, 4 patients received Dose A: pTreg expansion was noted in 2/4; 1 achieved clinical remission. 7 patients received Dose B: 1 developed a rash deemed a DLT; 2 achieved remission and 1 achieved response. pTreg expansion was noted in all patients at this dose. 5 patients received Dose C. No DLT was observed. pTreg expansion was seen in all patients in this group, but unwanted Tcon activation was also observed at this dose level. No patient achieved clinical response at this dose. Therefore, MTD was modified to maximum effective dose (MED) and Dose B was considered MED; 10 additional patients were enrolled: 2 achieved remission, 4 response, 2 had no response and 2 withdrew (headaches and worsening colitis). Overall, 38.4% (10/26) have achieved either response or remission including 53% in Dose B alone (9/17). Although all Dose B subjects had pTreg expansion, Treg expansion in the colonic mucosa was not necessary for clinical response. Conclusion LD SC IL-2 was well tolerated and associated with a biological response and pTreg expansion in patients with moderate-to-severe UC. 1x106 IU/m2 was found to be the MED.