November 2, 2012
The ITN’s Network Steering Committee convened last week in Washington, DC for our twice-annual meeting to update the ITN’s portfolio. Below is a summary of the content and discussion from this meeting.
Improved Outreach
In the State of the Network talk, Jerry Nepom, MD, PhD (ITN, Benaroya Research Institute) highlighted the ITN’s efforts over the past year to improve outreach to the scientific community. The ITN is increasingly utilizing its Strategic Assessment Groups for developing trial concepts, and as part of these efforts distributed two Requests for Proposals (RFPs) for transplant and allergy studies. Additionally, the launch of TrialShare later this month represents a huge step in data sharing and transparency, collaborative hypothesis generation, and specimen sharing between the ITN and the larger community. Adam Asare, PhD (ITN) provided an overview of the TrialShare system, and NSC members were able to try the system themselves at demo stations during breaks. TrialShare will be released to ITN stakeholders on October 29th, with full public roll-out on November 5th, 2012. Larry Turka, MD (Beth Israel) presented a summary of findings from an external advisory group that was commissioned by the ITN to review ITN Biomarker & Discovery Research operations, highlighting recommendations for more involvement of the academic community.
Clinical and Mechanistic Successes and Challenges
Deborah Phippard, PhD (ITN) and Peter Sayre, MD, PhD (ITN) highlighted clinical and mechanistic areas of focus for discussion by the NSC, including the A-WISH study in transplant; the LEAP study, GPAC study, GRASS study and cat challenge pilot studies in allergy, including plans to make use of a cat allergen chamber; the ACCESS and CALIBRATE studies in autoimmunity; and the JDRF Treg study, T1DAL study, and RETAIN studies in type 1 diabetes. For a full update on the ITN’s clinical and mechanistic portfolio, see here.
Stephen Gitelman, MD (University of California, San Francisco) also presented recently-acquired primary endpoint data from the START trial (Study of Thymoglobulin to Arrest Newly Diagnosed Type 1 Diabetes). Although ATG therapy did not delay beta cell destruction over 12 months, the ITN has begun to uncover a number of mechanistic explanations (notably, ratios of T-effector cells to T-regulatory cells) that will continue to be explored.
New to the Pipeline
The NSC reviewed and discussed two Full Applications at the October meeting. The first, from James Krueger, MD, PhD (The Rockefeller University), is for a combination study testing anti-IL-12/23 (ustekinumab, Janssen Biotech) followed by CTLA-4-IG (abatacept, Bristol-Myers Squibb) in Psoriasis subjects. Administering co-stimulatory blockade (abatacept) in the context of a reduced inflammatory milieu (as achieved via ustekinumab) is predicted to enable the establishment of tolerance. This concept arose out of discussions with the ITN’s Autoimmune Assessment Group to identify promising combination therapies for autoimmune diseases. Not only is this sequential treatment approach promising, but mechanistic analyses can be directly performed on the relevant organ (skin). The NSC was enthusiastic about this approach and the ITN will continue to develop this study.
The second Full Application was conceived as a collaboration between the ITN, TrialNet, and Genentech. The proposal, developed by Carla Greenbaum, MD (Benaroya Research Institute), Jane Buckner, MD (Benaroya Research Institute) and presented by Mario Ehlers, MD, PhD (ITN), is to study anti-IL6 receptor antibody (tocilizumab, Genentech) in new-onset type 1 diabetes. Anti-IL6R is known to be an important modulator of both the innate and adaptive immune systems, and thus may have promise for type 1 diabetes. Thus far no agent has been able to completely stop disease progression in type 1 diabetes, highlighting the need to test new therapeutics with different modes of action. The ITN also recognizes the potential of anti-IL6R to be combined with antigen-specific therapy in the future, and this study represents an important step towards that goal. The NSC agreed this is an important effort, and the ITN will continue to develop this study in collaboration with TrialNet and Genentech.
In addition to the two Full Applications, the NSC discussed progress on two other studies in the ITN’s pipeline. One of these studies, “Anti-TSLP (Amgen) plus antigen-specific immunotherapy for induction of tolerance in individuals with cat allergy” (Jon Corren, MD, University of California, Los Angeles) was presented to the NSC as a concept at previous meetings as the result of an industry (Amgen)-ITN assessment discussion, and has since been developed into a trial protocol. The NSC provided additional feedback on the protocol design that will be incorporated..
Larry Turka, MD (ITN, Harvard Medical School) presented the NSC with an update of the study, “Alemtuzumab, costimulation blockade and sirolimus: a tolerogenic canvas for donor antigen delivery” from Allan Kirk, MD (Emory University). This study uses mesenchymal stem cells (MSCs) as a source of donor antigen to promote tolerance to kidney transplants when used with the above-listed immunosuppression canvas. Since the initial review of this study at the April 2012 meeting, the ITN has modified the protocol to include multiple doses of MSCs (originally included just one), and will incorporate an assay to assess whether the MSCs are having an immunological effect. The NSC agreed these were good improvements.
Stephen Durham, MD (Imperial College London) presented a Concept Proposal from Liam O’Mahony, PhD (Swiss Institute of Allergy and Asthma Research) proposing the use of probiotics in combination with allergen immunotherapy to induce tolerance. This proposal arose from an ITN-issued RFP for “allergen +” combination therapies in allergy or asthma. NSC members were intrigued about the concept of probiotic therapies for augmenting tolerance induction and felt that we should more generally explore this area before we begin considering a specific study design.
Looking Ahead
As the ITN prepares for our new funding cycle as a cooperative agreement we will continue to make use of our Strategic Assessment Groups, partner with other organizations, make use of Academic Centers of Excellence and rely heavily on the collective and individual expertise within the Network Steering Committee to develop and conduct new innovative tolerance studies involving combinations of therapeutics, including the addition of antigen-specific therapy to other immune modulators, and other novel treatment approaches. We look forward to the public launch of TrialShare (itntrialshare.org) this month and our continued effort to make our repository samples broadly available.
If you have not yet done so, please return your completed NSC Questionnaire and any additional comments to Philip Bernstein (pbernstein@immunetolerance.org). Thanks to everyone for their hard work and participation in the October 2012 NSC meeting!
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