November 15, 2011
The members of the ITN’s Network Steering Committee (NSC) have played a very pivotal role in helping to shape the ITN’s pipeline over the past year. The fruits of these efforts were evident at this fall’s meeting, which included the review of three Full Applications and one concept proposal, in total representing each area of ITN focus (autoimmune, transplant, allergy, and type 1 diabetes). In his State of the Network address, Jerry Nepom, MD, PhD thanked the NSC for their continued efforts, and shared ITN highlights and accomplishments over the past year, including:
The rest of the meeting focused on the review of potential new trials, described in more detail below:
Allergy
The group reviewed a Full Application from Thomas Kündig, MD (University of Zurich) to support the mechanistic portion of a cat allergen vaccine study. The novel vaccine is designed to enhance antigen presentation via MHC pathways and is delivered directly to the lymph nodes. Dr. Kundig has clinical data demonstrating this therapy can induce tolerance after only three injections which would significantly reduce the burden of undergoing a full course of immunotherapy (usually requiring 3-5 years). The investigators are open to working with the ITN on the clinical study design to better facilitate a mechanistic strategy. This would be an opportunity to plan an innovative repertoire of assays to look at tolerance mechanisms.
Transplantation
Larry Turka, MD (ITN, Harvard Medical School) gave an update on the ITN’s transplant portfolio, breaking down transplant studies into three categories:
We have learned from previous trials that novel interventions such as mixed chimerism (i.e., using cellular therapies to create tolerance to donor) can induce tolerance in some instances, but achieving this can be complex. In an effort to identify novel interventional strategies, the ITN issued a targeted RFP to the transplant community which resulted in numerous high-quality proposals. Many of the proposals include innovative elements and the ITN will work with investigators to come up with a path forward.
For withdrawal trials, the ITN will need to consider the risks and benefits when weaning stable transplant recipients off low-dose immunosuppression. The NSC agreed that the transplant community will require a validated tolerance signature to be comfortable with complete drug withdrawal. The NSC reviewed a Full Application from Jim Markmann, MD (Massachusetts General Hospital) for a proposed study to identify a tolerance signature in liver transplant recipients prospectively weaned from immunosuppression. The study would help determine the proportion of liver transplant recipients who can achieve tolerance, as well as provide an opportunity to define molecular markers that distinguish the tolerant from non-tolerant patients.
As the transplant portfolio continues to evolve, the ITN will need to find the optimal balance of these three types of studies to fulfill the goal of achieving tolerance.
Type 1 Diabetes
Building from the mechanistic results of the Greenbaum trial (IL-2 plus Rapamycin in type 1 diabetes), Mario Ehlers, MD, PhD (ITN) presented a concept proposal for a dose-finding study using an IL-2 mutein (structurally modified version of IL-2 with reduced binding properties) in type 1 diabetes. The Greenbaum trial demonstrated that while the administration of IL-2 induced an increased production of Tregs, it similarly induced an increase in natural killer (NK) cells, which promote inflammation. One hypothesis is that using a modified version of IL-2 could promote induction of Tregs while preventing the induction of NK cells. ITN will continue to consider this strategy.
Autoimmunity
The NSC discussed a Full Application from Betty Diamond, MD (Feinstein Institute for Medical Research) for a combination study using rituximab (anti-CD20) plus belimumab (anti-BAFF) in lupus nephritis. This proposed combination of agents is hypothesized to first deplete the B cell population (using rituximab), and then follow rituximab treatment with belimumab to promote tolerogenic reconstitution of the B-cell population so it is less auto-reactive. The NSC agreed this was an innovative approach with a strong rationale for a patient population in need of better therapeutics.
“Data Liberation” through TrialShare
Adam Asare, PhD (ITN) gave a demonstration of the ITN’s newest data analysis and visualization tool, TrialShare. This dynamic, web-based program allows ITN/investigators to view study data and figures in an interactive manner. The program was well-received by the NSC and will be ready for launch in January 2012.
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