Inflammatory bowel disease (IBD), comprised of ulcerative colitis (UC) and Crohn's disease (CD) are chronic disorders of the GI tract with rapidly increasing prevalence. Despite recent advances in treatment, a significant proportion of patients have suboptimal responses to medical therapy, leaving an urgent need to identify new therapies. One promising new approach to treat IBD is through the manipulation of regulatory T cells (Tregs). Tregs are an immune modulating subset of CD4+ lymphocytes that antagonize the activation and effector function of multiple immune cell types and promote tolerance to self-antigens. Adoptively transferred Tregs are effective in murine models of IBD. An alternative approach to disease management through Treg manipulation is to increase Treg numbers in vivo. Interleukin-2 (IL-2, Proleukin) is a T cell growth factor. IL-2 is currently licensed for the treatment of metastatic renal cell carcinoma and metastatic melanoma. At low doses, IL-2 promotes the selective activation and expansion of Tregs in humans. Tregs constitutively express CD25, a component of the high-affinity IL-2R, while CD25 is only transiently expressed by activated conventional T effector cells. Low-dose (LD) IL-2 selectively expands Tregs in humans and is safe in chronic GvHD and other phase 1 and 2 clinical trials. We recently published that LD IL-2 is protective in a humanized mouse model of IBD. Based on this preclinical data, we initiated and have almost completed a Phase 1b/2a clinical trial of LD IL-2 in 24 patients with UC. Subcutaneous (sc) LD IL-2 is well tolerated and associated with a biological response and pTreg expansion in UC: overall, 41.6% of patients have achieved either response or remission including 60% of patients treated with the maximum effective dose (MED). With this exciting data, we have developed a Phase 1b/2a clinical trial to assess the safety and the efficacy of LD SC IL-2 for the treatment of CD and to study the immunoregulatory effects of IL2 in the peripheral and mucosal immune compartments. To date, we have obtained: 1) provisional IRB approval; 2) an Investigational New Drug (IND) approval from the FDA; 3) support from commercial entities to supply drug free of charge to patients. We have designed a comprehensive immunophenotyping strategy to assess the biological effects of LD IL-2 and to correlate these findings with clinical outcomes. In this study we propose:
Aim 1 : To determine the safety of sc LD IL-2 in the treatment of moderate-to-severe CD. We propose a phase 1b/2a clinical trial of daily sc LD IL-2 for 8 weeks in CD patients to determine the maximum effective dose (MED) and safety profile, and to assess a signal of efficacy.
Aim 2 : To determine in CD patients whether sc LD IL-2 modulates peripheral blood and lamina propria Tregs in vivo and correlates with clinical outcome. We will perform deep immunophenotyping in CD patients treated with LD IL-2 and comprehensively assess the effects of LD IL-2 on CD4+ Tregs and other immune cells in both peripheral and mucosal compartments, and correlate changes in immune phenotype with clinical outcome. Overall this trial is designed to determine the MED and safety profile of LD IL-2 in CD, to obtain a signal of efficacy, and to assess mechanistic underpinnings.
Interleukin-2 (IL-2, Proleukin) is a T cell growth factor. IL-2 is licensed for the treatment of metastatic renal cell carcinoma and metastatic melanoma and at low doses, 100-times lower than those used in cancer therapy, IL- 2 promotes the selective expansion of regulatory T cells (Tregs) in humans. Our preliminary data in a phase 1b/2a clinical trial indicates that low-dose IL2 appears safe in ulcerative colitis patients, expands Tregs in the blood, and is associated with a biological response. In this study, we aim to assess the safety of and immune effects of low-dose IL-2 to selectively expand Tregs in vivo in patients with moderate-to-severe Crohn's disease, with the aim that this expansion will be associated with a therapeutic response.
