May 30, 2014
The first Network Steering Committee (NSC) meeting under the ITN’s new UM1 grant took place this past week in Seattle, WA. During the past year, the ITN has been planning for this transition and worked closely with the newly-formed Therapeutic Area Assessment Groups to crystallize the strategic plans for pursuing tolerance over the next few years. Although we have received generous funding from NIAID, our resources are nonetheless limited and, thus, we must selectively “place our bets” on the most promising approaches to make a real impact on the field. This has been the focus of the assessment groups in developing their strategic plans.
During the first day of the meeting each of the Assessment Groups (Allergy, Autoimmune, Transplant, and Type 1 Diabetes) had the opportunity to meet individually to finalize the strategic plan for each area, and reported back to the entire group on the second day:
For allergy and asthma, ITN will focus on “providing cutting-edge assays that evaluate changes in the immune response to allergens in the context of experimental therapy. ITN clinical studies will pioneer the concept of “allergen-plus”, in which novel immunomodulators and immune targets are assessed in combination with specific allergen immunotherapy.”
For autoimmunity the challenge will be developing mechanistic hypotheses and therapeutic strategies suited to a heterogeneous group of diseases. As such, the ITN “will prioritize studies in a few selected autoimmune diseases, building on previous experience, prioritizing diseases with a relevant antigen (whether self or microbial in origin) that can be targeted and monitored, and/or diseases with accessible tissue. Priority will be given to studies that evaluate combinations of agents that induce immune deviation and/or regulation, produce effector cell depletion or exhaustion, to achieve durable clinical remission of disease.”
Transplant has the advantage of a known inciting antigen and so ITN “will prioritize interventional studies that explore selected strategies for safely and reliably inducing robust and durable transplantation tolerance via a combination of deletion of alloreactive cells and promotion of antigen‐specific regulatory cells.”
Type 1 diabetes, like other autoimmune diseases, will likely require multiple therapeutics to durably reverse immune dysregulation. As such, ITN “will prioritize studies in recent‐onset T1D that evaluate combinations of agents that induce immune immunomodulation (e.g., through deviation and regulation mechanisms) with agents that interrupt effector cell activity (e.g., through depletion or exhaustion mechanisms), to achieve durable preservation of beta cell function.”
While the therapeutic-area strategic plans had been written independently, they have a number of common themes. These include (but are not limited to):
The ITN’s directive is to now transition from the planning phase to implementation, and identify the trials to initiate in 2015. Assessment Groups will be convening again on monthly teleconferences in the near future to execute these plans and select priority trials. Each group will plan for two concepts for development in 2015.
During the meeting, the NSC also heard two presentations on novel mechanistic assays for immune monitoring:
Eric Wambre, PhD (Benaroya Research Institute) presented recent data on the use of tetramers to track allergen-specific immune responses. Using these tetramers, his group found that CD27- allergen-specific T cells are associated with allergic disease (consistent across multiple allergy types), and that allergen immunotherapy using grass pollen results in a reduction of the pathologic response and selective elimination of the CD27- T cell subset. He also demonstrated other assays that allow quantitation of allergen-specific T cells in small blood samples that may be a surrogate of successful immunotherapy for clinical trials.
Megan Sykes, MD (Columbia University) presented on the use of deep sequencing to track donor-reactive T cells in transplant. Using pre-transplant samples from patients in the ITN’s Mixed Chimerism trial, the investigators sequenced the CDR3 region of T cells that proliferated in response to anti-donor reactions, and then tracked these clones post-transplant. They found that donor-reactive T cell cones were reduced in tolerant patients (N=3), in contrast with two conventional (non-tolerant) transplant recipients who showed expansion of donor-reactive clones. This data suggests clonal deletion may be a potential mechanism of allograft tolerance, as well as demonstrates a new assay to track donor-reactive T cells.
Presentations from the NSC meeting are available on Sharepoint (remember the confidential nature of this data).
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