The Immune Tolerance Network’s (ITN) “Learning Early About Peanut” (LEAP) study was the first randomized trial to prevent food allergy in a large cohort of high-risk infants. The results of the study, published in the New England Journal of Medicine and available on TrialShare, demonstrated that consumption of a peanut-containing snack by infants who were at high-risk for developing peanut allergy prevented the subsequent development of allergy.
Over 600 children between 4 and 11 months of age at high risk for peanut allergy were randomized to either consume or avoid peanut until age 5 in order to compare the incidence of peanut allergy. Of the children who avoided peanut, 17% developed peanut allergy by the age of 5 years. Remarkably, only 3% of the children who were randomized to eating the peanut snack developed allergy by age 5 – an 81% reduction of the incidence of peanut allergy development. Therefore, in high-risk infants, sustained consumption of peanut beginning in the first 11 months of life was highly effective in preventing the development of peanut allergy.
The movement towards improved clinical trial transparency is steadily growing, driven forward by the scientific and ethical concerns raised by significant underreporting of clinical trial results. True transparency requires complete access to trial data and analytic strategies in accessible formats so that results can be verified and extended. In November 2012, the ITN launched the TrialShare platform (itntrialshare.org), marking a revolutionary step forward in fulfilling this vision of true clinical trial transparency. ITN TrialShare allows unfettered access to ITN clinical trial data and analysis code. The system also provides access to the ITN specimen repository catalog, allowing investigators from the research community to request specimens for follow-up experiments.
With the publication of results from the pivotal RAVE study in the New England Journal of Medicine (NEJM), ITN achieved a significant milestone demonstrating TrialShare’s potential for supporting online, interactive manuscripts. The publication included direct links to the associated subject-level data, analysis code and supporting documentation. In an accompanying editorial to the paper, ITN TrialShare was highlighted as part of the “new frontier” in participant level data transparency.
ITN TrialShare won the 2014 National Academies Board on Research Data and Information Challenge, themed "Using Data for the Public Good." TrialShare also received honorable mention from the Bio-IT World’s Best Practice Awards in 2013.
In April 2011, the FDA approved Rituximab (anti-CD20; Genentech) for use in granulomatosis and microscopic polyangiitis based on results published in The New England Journal of Medicine and available on TrialShare from the ITN's RAVE study. Before the Rituximab label extension, the standard of care for this disease was cyclophosphamide, a potent immunosuppressant that although effective, is very toxic when used long-term. The RAVE study was able to successfully compare a potentially safer biologic therapy for a rare and challenging disease against the long-accepted standard of care treatment. Designing such a study required creative approaches which are described in the November 2011 edition of the Open Arthritis Journal, “Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) Trial” (Specks et al.). In this paper the authors “illuminate the unique challenges involved in comparing a new treatment approach against an entrenched standard of care.”
A core principle of the ITN is that detailed clinical monitoring coupled with extensive mechanistic laboratory studies will uncover clues about the pathways underlying tolerance, leading to improved therapeutics. In an ITN study representing a large cohort of operationally tolerant kidney transplant recipients, Dr. Kenneth Newell (Emory University) and collaborators — using ITN Core Facilities and data analysis capabilities — identified a B cell signature (both cellular and genetic) in patients that withdrew from immunosuppression without organ rejection. When applied to a separate blinded set of samples, this signature was able to very accurately predict which samples were associated with tolerance (off drugs without signs of rejection) as compared with ongoing immunosuppression (on drugs).
As long as 25 years ago in mice, and more recently in pigs and non-human primates, investigators have been able to induce renal allograft tolerance by a combined kidney and bone marrow transplant from the same donor. This approach uses a bone marrow transplant to create a temporary environment comprised of mature hematopoietic cells from both donor and recipient, termed “mixed chimerism,” that may be more hospitable to the donor kidney and help prevent rejection. The ITN is exploring this strategy in human trials, including the use of a non-myeloblative preparative regimen for induction of mixed chimerism that was tested in a pilot trial on five patients with investigator Dr. David Sachs (Harvard Medical School), who pioneered the animal model.
Molecules on lymphocyte cell surfaces provide an attractive set of potential targets for therapeutic strategies that mimic natural mechanisms of anergy, deletion, and functional deviation. The ITN has led a number of exploratory and pivotal clinical trials in autoimmune diseases, including studies of anti-CD3 in type 1 diabetes and psoriatic arthritis, CTLA4-Ig in multiple sclerosis and systemic lupus erythematosus, as well as partnered with TrialNet in evaluating anti-CD20 therapy for type 1 diabetes. These therapeutic approaches induce regulatory effects on immune cells favoring a rebalancing of the immune system and disease quiescence.
"Getting patients off immunosuppressive drugs safely is a key objective of ITN transplant trials." In a recent ITN study of 20 pediatric liver transplant recipients, Dr. Sandy Feng (University of California, San Francisco) successfully weaned 12 of 20 young children from immunosuppression while maintaining normal graft function without rejection, offering tremendous hope for these young patients to live drug-free. The ITN will continue to refine this immunosuppression withdrawal protocol in pediatric liver transplantation and identify predictive signatures of tolerance with the hope of extending these treatment benefits to more children, and potentially adults.
In a pioneering multi-center international study of islet transplantation, the ITN and Dr. James Shapiro (University of Alberta) evaluated the merits of the Edmonton Protocol to help patients with difficult-to-control type 1 diabetes. Several patients receiving islet transplants through this protocol exhibited partial islet function with safe and successful stabilization of blood sugar levels. Building on this success, the ITN has recently launched a major initiative in type 1 diabetes to find drugs with different modes of action that when used in combination will enhance and complement each other to promote efficacy. In collaboration with JDRF, the ITN has commissioned a multi-center network of research laboratories to perform preclinical screening of combination therapy, as well as a consortium of clinical sites to conduct innovative type 1 diabetes studies of novel therapies that induce immune tolerance and block disease progression soon after initial diagnosis.
