May 4, 2012
The proposals discussed at the April 2012 ITN Network Steering Committee (NSC) Meeting in Chicago all were trials that utilize a combination of therapeutics, representing a commitment by the ITN to address the complexity of the immune system using innovative approaches. These proposals were all developed out of the ITN’s strategic assessment initiatives which tap the NSC’s expertise to identify and define the best ideas for tolerance trials.
The recommendation to move ahead on the following proposals reflects the ITN’s mandate to be bold, innovative, and to conduct trials that no one else would. Details below:
Anti-TSLP plus allergen extract for cat allergy
About a year ago the ITN’s Tolerance in Allergy and Asthma (TAA) subgroup proposed a strategy, referred to as “antigen +,” to combine immunotherapy with an immune modulator to convert desensitization to tolerance. This study is an example of this “antigen +” strategy, and will combine cat allergen immunotherapy with blockade of TSLP, a cytokine that is involved in allergic disease, as a means of creating durable tolerance to cat. Investigator Jon Corren, MD (University of California, Los Angeles) presented an outline for the study, which has been developed collaboratively with the ITN and Amgen, the manufacturer of anti-TSLP. The NSC agreed this study has a strong rationale and ITN will continue its development.
Combination therapies in autoimmune diseases
Over the past few months the members of the ITN’s Autoimmune Assessment Group identified potential combinations of drugs with mechanistic and clinical rationale for various autoimmune indications. The goal of these combination approaches is to increase regulation while decreasing effector responses, which ideally will lead to tolerance. One of these proposals has matured to the level where the NSC recommended that a Full Application be evaluated.
The proposal, developed by James Krueger, MD, PhD (Rockefeller University), uses sequential treatment with ustekinumab (anti-IL12/23) and abatacept (CTLA4-IG) in psoriasis. The idea is to reduce the pro-inflammatory environment with ustekinumab (silences T-cell derived cytokines), and add costimulatory blockade (CTLA4-IG) so that the lymphocytes that are reactivated by antigen-presenting cells do not develop into autoreactive T-cells. The NSC agreed this represented a logical approach to tolerance in psoriasis and is consistent with the ITN’s combination therapy strategy to target multiple arms of the immune system.
Mixed chimerism in kidney transplantation
To build upon the success of David Sachs’ earlier ITN mixed chimerism/kidney transplant trials, the ITN issued a Request for Proposals for trials that employ therapeutic cell transfers (e.g., bone marrow, Tregs, etc.) in combination with solid organ transplantation. A number of proposals in response to this RFP are at various stages of consideration.
The application from Lode Swinnen, MD and colleagues (Johns Hopkins University) employs high-dose post-transplant cyclophosphamide for combined bone marrow and kidney transplant. High-dose cyclophosphamide will selectively deplete activated, alloreactive host and donor T cells. The resulting mixed donor cell chimerism is expected to facilitate solid organ engraftment. They have successfully employed this regimen in numerous bone marrow transplant recipients, and propose this as a platform to induce tolerance in kidney transplantation. The NSC was impressed with the clinical results in non-kidney transplant settings, and agreed it has a strong rationale for tolerance and recommended that we proceed to protocol development.
We will continue to work with investigators on other proposals for further consideration by the Network Steering Committee.
Other Portfolio Updates
The meeting also included a clinical and mechanistic portfolio update from Deborah Phippard, PhD and Peter Sayre, MD, as well as some potential plans for a mechanistic pilot study to support cat allergy trials in the ITN pipeline, including the anti-TSLP study discussed above.
New faces to the NSC this year include Kathryn Wood, PhD (University of Oxford), and James Markmann, MD, PhD (Massachusetts General Hospital). The ITN is grateful to have their expertise and perspective as part of the NSC.
Thanks to everyone who came and helped make the meeting a success!
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