Project 1: Preventing Acute GVHD and Treating Chronic GVHD in a Canine Model

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ABSTRACT - PROJECT 1 A recent comprehensive analysis of outcomes among the first 1,092 patients with advanced hematologic malignancies transplanted under the auspices of current Projects 2 and 3 showed that one-fifth of patients died of graft-vs.-host disease (GVHD)-related causes. The analysis further showed that acute GVHD had no statistically significant associations with GVT effects. This suggested that avoiding acute GVHD would reduce the risk of non-relapse mortality (NRM) without increasing the risk of relapse. In contrast, chronic GVHD was highly significantly associated with GVT effects; however, this benefit was offset by NRM, which was largely due to infections occurring during the lengthy period of treatment for chronic GVHD. So the challenge is not to prevent chronic GVHD, since that might increase the risk of relapse, but to treat it more effectively so that both the duration of treatment and the associated risks of morbidity and NRM are reduced while GVT effects are maintained. The proposed studies will use a DLA-mismatched canine hematopoietic cell transplantation (HCT) model that has a long-standing track record of translating novel acute GVHD prevention and treatment into the clinic. Moreover, we have now established the only simple, reproducible, and clinically relevant large animal model of chronic GVHD. Having reproducible models of both acute GVHD and of chronic GVHD places us in a unique position to better understand, treat, and prevent GVH reactions. In these two canine models, T-cell activation occurs as it does clinically in human patients, despite standard postgrafting immunosuppression, which then results in either acute or chronic GVHD. Linked mechanistic studies will tell us about unique phenotypic and functional T-cell signatures that will be predictive of quiescence or of GVHD and might be targets of therapeutic interventions. In the current funding period, we have developed a unique set of canine- specific monoclonal antibodies (mAbs) and fusion proteins interacting with regulatory cell-surface determinants on T-cells that hold promise of enabling more-specific interventions in immune responses than have been possible with current pharmacological immunosuppression. We expect to be guided in the proposed therapeutic studies by mechanistic studies which might determine the time of upregulation of T-cell-specific antigens that have: ▪ Costimulatory function which may be blocked; ▪ Down-regulatory function that can be activated; or ▪ No regulatory function, but which can be used as targets for radioimmunotherapy. We believe that the proposed rational use of biologic agents to prevent acute GVHD and to treat chronic GVHD is highly novel and, moreover, that therapy successful in the canine model can be translated to benefit human patients transplanted under the auspices of Projects 2 and 3.