Low Dose IL-2 for Crohn's Disease
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Boston Children's Hospital
Must not be taking: Biologics
Disqualifiers: Ulcerative colitis, Cancer, HIV, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?The purpose of this study is to determine the safety and maximum effective dose (MED) of Interleukin-2 in subjects with moderate-to-severe crohn's disease.
Will I have to stop taking my current medications?
The trial requires that you have stable doses of your current medications. However, if you are taking any biologic medication, you must stop it at least 4 weeks before starting the study drug.
What evidence supports the effectiveness of the drug Interleukin-2 (IL-2) for treating Crohn's disease?
Research shows that low-dose IL-2 has been effective in treating other inflammatory conditions like ulcerative colitis in mice by reducing inflammation and improving gut health. This suggests it might also help with Crohn's disease, which is another inflammatory bowel condition.
12345Is low dose IL-2 generally safe for humans?
Low dose IL-2 has been studied in various conditions, and while it can cause side effects like fever, nausea, and mild low blood pressure, these are generally reversible. However, higher doses have been linked to more severe issues like gastrointestinal problems and cardiovascular toxicity, so careful monitoring is important.
56789How does the drug IL-2 differ from other treatments for Crohn's Disease?
IL-2 (Interleukin-2) is unique because it works by stimulating the immune system, specifically by promoting the growth and activity of certain immune cells like T cells, which is different from many other treatments for Crohn's Disease that primarily aim to suppress the immune response. This approach could potentially offer a novel way to manage the disease by enhancing the body's natural immune functions.
45101112Eligibility Criteria
Adults aged 18-80 with moderate-to-severe Crohn's Disease, not responding to conventional therapies, can join this trial. They must have endoscopic inflammation and no recent biologic medication use. Exclusions include other bowel diseases, significant infections or lab abnormalities, certain cancers within 5 years, pregnancy, and inability to consent.Inclusion Criteria
My Crohn's disease is moderate to severe.
Evidence of endoscopic inflammation accessible via ileocolonoscopy or ileoscopy
I have not improved with standard treatments for my condition.
+9 more
Exclusion Criteria
I have had cancer other than non-melanoma skin cancer in the last 5 years.
I do not have any serious infections right now.
Significant laboratory abnormalities;
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive an 8-week course of once-daily, subcutaneously administered IL-2 to determine the maximum effective dose and safety profile
8 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment, including changes in immune cells
4 weeks
Participant Groups
The trial is testing the safety and maximum effective dose of Interleukin-2 (aldesleukin) for treating Crohn's Disease. It aims to find out how well it works in patients who haven't had success with standard treatments.
1Treatment groups
Experimental Treatment
Group I: Interleukin-2Experimental Treatment1 Intervention
Study drug: Interleukin-2 (aldesleukin, Proleukin, IL-2).
Each subject will receive an 8-week course of once-daily, subcutaneously administered IL-2. There will be two dose cohorts. Each subject will be recruited into a single dose cohort and receive a single dose level of IL-2 throughout the study.
The dose levels will be as follows:
Cohort 1: 1.0x10\^6 IU/m\^2/day. Cohort 2: 1.25x10\^6 IU/m\^2/day.
Interleukin-2 is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Aldesleukin for:
- Metastatic melanoma
- Metastatic renal cell carcinoma
🇪🇺 Approved in European Union as PROLEUKIN for:
- Metastatic renal cell carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Brigham and Women's HospitalBoston, MA
Boston Children's HospitalBoston, MA
Mount SinaiNew York, NY
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Who Is Running the Clinical Trial?
Boston Children's HospitalLead Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Collaborator
National Institutes of Health (NIH)Collaborator
References
The effect of treatment on lymphokine-secreting cells in the intestinal mucosa of children with Crohn's disease. [2019]Recent studies have shown both interleukin 2 (IL-2) and interferon gamma (IFN) to be elevated in patients with active Crohn's disease compared to ulcerative colitis or non-inflammatory bowel disease controls. However the effect of treatment on these lymphokines has not been studied.
Interleukin 2 activity of human intestinal mucosa mononuclear cells. Decreased levels in inflammatory bowel disease. [2013]Interleukin 2, a soluble product of activated T lymphocytes, is of central importance in the development of an appropriate T-cell immune response. Defects in the production of or response to this lymphokine have been described in a variety of immune deficiency and autoimmune states, thus suggesting a role in the pathogenesis of such disorders. To investigate potential abnormalities of interleukin 2 in inflammatory bowel disease, we measured its activity in cultures of intestinal mucosa mononuclear cells derived from Crohn's disease and ulcerative colitis patients. Lamina propria mononuclear cells from inflamed and control tissues were incubated with phorbol myristate acetate, and the amount of the lymphokine in the supernatants was quantitated in a biological assay using cloned, interleukin 2-dependent, cytotoxic mouse T-cell lines. We found that, in culture supernatants of cells from both forms of inflammatory bowel disease, interleukin 2 levels were significantly lower than those detected in cultures containing cells from histologically normal mucosa. Low levels were not correlated to duration, clinical activity, and anatomical location of the disease process or corticosteriod therapy. Deficient activity of this essential growth factor could contribute to abnormal T-cell proliferation and clonal expansion at the gut mucosal level, perhaps inducing a defective immune response leading to a chronic inflammatory reaction in Crohn's disease and ulcerative colitis.
Low-dose interleukin-2 alleviates dextran sodium sulfate-induced colitis in mice by recovering intestinal integrity and inhibiting AKT-dependent pathways. [2021]Several phase 1/2 clinical trials showed that low-dose interleukin-2 (IL-2) treatment is a safe and effective strategy for the treatment of chronic graft-versus-host disease, hepatitis C virus-induced vasculitis, and type 1 diabetes. Ulcerative colitis (UC) is a chronic inflammatory condition of the colon that lacks satisfactory treatment. In this study, we aimed to determine the effects of low-dose IL-2 as a therapeutic for UC on dextran sulfate sodium (DSS)-induced colitis. Methods: Mice with DSS-induced colitis were intraperitoneally injected with low-dose IL-2. Survival, body weight, disease activity index, colon length, histopathological score, myeloperoxidase activity and inflammatory cytokine levels as well as intestinal barrier integrity were examined. Differential gene expression after low-dose IL-2 treatment was analyzed by RNA-sequencing. Results: Low-dose IL-2 significantly improved the symptoms of DSS-induced colitis in mice and attenuated pro-inflammatory cytokine production and immune cell infiltration. The most effective dose range of IL-2 was 16K-32K IU/day. Importantly, low-dose IL-2 was effective in ameliorating the disruption of epithelial barrier integrity in DSS-induced colitis tissues by restoring tight junction proteins and mucin production and suppressing apoptosis. The colon tissue of DSS-induced mice exposed to low-dose IL-2 mimic gene expression patterns in the colons of control mice. Furthermore, we identified the crucial role of the PI3K-AKT pathway in exerting the therapeutic effect of low-dose IL-2. Conclusions: The results of our study suggest that low-dose IL-2 has therapeutic effects on DSS-induced colitis and potential clinical value in treating UC.
Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer. [2018]Recombinant interleukin-2 (IL-2) products (e.g. aldesleukin, teceleukin) are nonglycosylated, modified forms of the endogenous compound. IL-2 acts as a pleiotropic mediator within the immune system, having a variety of effects via specific cell surface receptors. The interaction of IL-2 with the IL-2 receptor induces proliferation and differentiation of a number of T lymphocyte subsets, and stimulates a cytokine cascade that includes various interleukins, interferons and tumour necrosis factors. Antitumour effects of IL-2 appear to be mediated by its effects on natural killer, lymphokine-activated killer (LAK) and other cytotoxic cells. In vivo and in vitro effects of IL-2 seem to be dependent to a large extent on the environment; many studies have reported conflicting results, perhaps due to diverse populations of effector cells, the availability of other cytokines that have synergistic or inhibitory influences, and the dosage regimens used. The recombinant products appear to be biologically indistinguishable from native IL-2 in vitro and in vivo; the former induce minor antibody formation but this does not appear to alter functional properties. In patients with metastatic renal cell carcinoma, IL-2 therapy achieves average objective response rates of 20% (range 0 to 40%), with a complete response rate of about 5% (range 0 to 19%). Response duration varies considerably but can be durable (lasting for > 12 months), with some patients remaining in complete response for > 60 months. It is unclear at present whether higher dosage regimens improve clinical response, or whether combination therapy with other agents and/or adoptive therapy is beneficial. Survival duration may depend on the risk factors present, with poorer performance status and more than one site of metastases associated with shorter survival times. Patients with metastatic malignant melanoma receiving IL-2 as monotherapy show an average objective response rate of 13% (range 3 to 24%); however, objective response rate averages 30% (range 4 to 59%) when IL-2 is used in combination with other agents. Overall median survival appears to be about 10 months. Preliminary data indicate that IL-2 produces a lower response rate in patients with refractory colorectal carcinoma, ovarian cancer, bladder cancer, acute myeloid leukemia or non-Hodgkin's lymphoma. Adverse effects accompanying high dose, intravenous IL-2 therapy can be severe, with cardiovascular, pulmonary, haematological, hepatic, neurological, endocrine, renal and/or dermatological complications frequently requiring doses to be withheld.(ABSTRACT TRUNCATED AT 400 WORDS)
Recombinant interleukin-2: a biological response modifier. [2007]The chemical properties, pharmacology, immunology, pharmacokinetics, clinical trials, adverse effects, and dosage and administration of recombinant interleukin-2 are reviewed. Recombinant interleukin-2 is an immunomodulating agent that stimulates the proliferation, activation, and differentiation of T and B cells, natural killer cells, and thymocytes. Two recombinant interleukin-2 products, aldesleukin and teceleukin, have been extensively studied. Most clinical experience with recombinant interleukin-2 has involved the treatment of renal cell carcinoma, melanoma, and colorectal cancer with a National Cancer Institute protocol. Patients with renal cell cancer and melanoma, who historically respond poorly to conventional therapy, have responded to therapy with recombinant interleukin-2. Recombinant interleukin-2 has been administered alone and in combination with lymphokine-activated killer cells, tumor-infiltrating lymphocytes, and interferons alfa and beta. In addition, the effect of dosage, administration rate, dosage schedule, route of administration, and cyclophosphamide pretreatment have been investigated. The adverse effects of recombinant interleukin-2 are generally reversible but are frequently severe and dose-related. Dose-limiting adverse effects include hypotension, edema, and renal dysfunction. Since hemodynamic monitoring and supportive care are essential, recombinant interleukin-2 should be administered in a critical-care setting by trained personnel. Recombinant interleukin-2 represents an advance in the therapy of renal cell cancer and melanoma and offers a new approach to the treatment of other refractory or recurrent malignancies.
Unusual gastrointestinal complications of interleukin-2 therapy. [2019]Minor and reversible gastrointestinal side effects are common when patients receive interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. We treated 42 cancer patients with IL-2 therapy and 3 patients developed serious gastrointestinal problems during treatment. Complications included sigmoid colon perforation, ischemic necrosis of the small and large intestine, and diffuse bowel ulceration. These were not associated with tumor implants or hypotension. Two patients died as a direct result of these problems despite aggressive surgical and medical management. The incidence of major gastrointestinal complications with IL-2 therapy may be greater than previously reported and a heightened awareness of potential gastrointestinal problems may circumvent considerable morbidity and mortality.
Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program. [2021]High-dose interleukin-2 (IL-2) has been FDA-approved for over 20 years, but it is offered only at a small number of centers with expertise in its administration. We analyzed the outcomes of patients receiving high-dose IL-2 in relation to the severity of toxicity to ascertain if response or survival were adversely affected.
Colonic perforation. An unusual complication of therapy with high-dose interleukin-2. [2019]The majority (85%) of patients receiving high dose Interleukin-2 (IL-2) experience gastrointestinal side effects, namely nausea, vomiting and diarrhea. In this article we describe four cancer patients that developed localized necrosis or perforation of the colon during IL-2 treatment. They represent 1.3% of patients (n = 315) or 0.9% of treatment courses (n = 452). All underwent surgical intervention and survived to leave the hospital. No common etiologic factor was apparent. Two patients were subsequently retreated with IL-2 without complication. Localized colonic necrosis or perforation is a rare complication associated with high dose IL-2 treatments. Aggressive surgical intervention is advocated and retreatment following recovery is safe.
A phase I study of interleukin-2 in children with cancer and evaluation of clinical and immunologic status during therapy. A Pediatric Oncology Group Study. [2019]The authors performed a Phase I study to assess the toxicity and hematologic effect of recombinant human interleukin-2 (rIL-2) in seven children with advanced malignancies. The rIL-2 was given as a bolus injection of 1 or 3 X 10(6) U/m2/dose three times a week (Monday, Wednesday, and Friday) for 3 weeks. No life-threatening toxicity occurred with the dose of 1 X 10(6) U/m2 of rIL-2. At a dose of 3 X 10(6) U/m2, therapy had to be terminated due to cardiovascular toxicity in two patients. Toxic effects at low-dose rIL-2 included fever, nausea, vomiting, and mild hypotension. High-dose rIL-2 toxicity included fluid retention, increased creatinine, oliguria, elevated liver enzymes, and significant hypotension. Immunologic studies showed that rIL-2 caused a drop in the number of circulating peripheral blood mononuclear cells, T-cells, and natural killer cells which returned to pretherapy levels or above by 24 to 48 hours. The rIL-2 exerted no growth or stimulatory activity on the leukemic cell population. To the authors' knowledge, this is the first report of a Phase I study of IL-2 therapy in children.
Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog. [2013]Recombinant interleukin-2 (IL-2) (aldesleukin, Proleukin, Chiron, Emeryville, CA) is approved for treatment of cancer patients and under investigation in HIV-infected individuals. However, treatment with aldesleukin is associated with toxicity, which may be due to its elicitation of inflammatory mediators from cells that express the intermediate-affinity IL-2 receptor. BAY 50-4798, a novel IL-2 analog, is a selective agonist for the high-affinity receptor. It induces the proliferation of activated T cells with a potency similar to that of aldesleukin but has reduced activity on cells expressing the intermediate-affinity receptor. In the current study, we compared cytokine responses elicited in peripheral blood mononuclear cell (PBMC) cultures stimulated with BAY 50-4798 or aldesleukin. BAY 50-4798 induced approximately 5-fold lower mean levels of endogenous IL-2 than aldesleukin, and at least 50% lower levels of proinflammatory cytokines, such as tumor necrosis fctor-alpha (TNF-alpha), IL-1beta, IL-6, and interferon-gamma (IFN-gamma). Furthermore, statistically significant reductions in the levels of IL-5, IL-8, IL-10, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were observed in response to BAY 50-4798. These findings increase our understanding of the biologic action of BAY 50-4798 and suggest a mechanism by which it may exhibit better safety than aldesleukin in humans.
Hypersensitivity to aldesleukin (interleukin-2 and proleukin) presenting as facial angioedema and erythema. [2016]Aldesleukin is a human recombinant interleukin-2 product. It also is known as interlukin-2 and Proleukin in the United States. It is indicated for the treatment of adults with metastatic renal cell carcinoma as well as for adults with metastatic melanoma. However, its use has been limited because of severe systemic toxicity. There have been no reports of aldesleukin producing a hypersensitivity reaction. This is the first reported case of an immediate systemic hypersensitivity reaction occurring after aldesleukin administration confirmed by enzyme-linked immunosorbent assay for specific immunoglobulin E against aldesleukin.
Feasibility of high-dose interleukin-2 in heavily pretreated pediatric cancer patients. [2020]The administration of high-dose interleukin-2 (IL-2) seems to be a therapeutic option for children with refractory and metastatic solid malignancies.