A fundamental gap exists between acute graft-versus-host disease (GVHD) rates (up to 50%) and the related mortality (up to 50%) following allogeneic hematopoietic stem cell transplantation (HSTC) and the paucity of therapies and biological correlative studies offered. This gap represents an important problem, because until it is filled, therapies will be limited to the nonspecific steroidal targeting of effector cells. Our ong-term goal is to identify and validate GVHD biomarkers with the potential for risk stratification an therapeutic targeting. Our objective in this application is to investigate early biomarkers of responsiveness to GVHD therapy that are drug targetable as well as biomarkers that can predict occurrence of GVHD. Our central hypothesis is that (i) a plasma biomarker panel, including suppression of tumorigenicity 2 (ST2), predicts responsiveness to GVHD therapy and survival, (ii) ST2, the lead candidate, can also predict GVHD before the clinical signs appear, (iii) ST2 can be targeted with antibodies to alleviate GVHD, and (iv) that the ST2/IL33 pathway is important in the pathology of GVHD. This hypothesis was formed based on our preliminary data (i) characterizing a panel of nine biomarkers that predict the day 28 response and the day 180 post-treatment survival when measured at initiation of therapy, (ii) showing that ST2 measured at day 14 post-HSCT predicts GVHD by day 100, (iii) showing that the murine anti-ST2 chimeric antibody prevents GVHD in an irradiated mouse model of GVHD, and (iv) showing that human CD4+ Th2 differentiation in the presence of IL33 is decreased in the presence of ST2 but is restored following treatment with human anti-ST2 neutralizing Ab. The rationale for this study is that once we are able to identify patients who will not respond to traditional treatments and who are at particularly high risk for subsequent morbidity and mortality, we can propose personalized treatment plans that are most effective if introduced early and targeted. This hypothesis will be tested with three specific aims: 1) Test ST2 and other drug-targetable candidate biomarkers for prediction of responsiveness to GVHD treatment in GVHD pre-treatment patient samples from two independent sets. 2) Test ST2 and other drug-targetable candidate biomarkers for prediction of acute GVHD occurrence and 6 month non-relapse mortality when tested early post-transplant. 3) Determine the effect of inhibiting the interaction between ST2 and IL33, its only known ligand, as proof-of-principle of a drug targetable GVHD biomarker. The proposed research is significant because the identification of therapy-resistant GVHD biomarker panels at symptom onset is expected to enhance our ability to risk-stratify patients before initiating GVHD treatment, and will guide the intensity and duration of treatment. The ability to identify patientsat high risk for GVHD early in their transplant course before GVHD development will allow for preemptive interventions. Ultimately, the proposed research may result in the discovery of a GVHD-specific drug, which will target the appropriate effector T cells to increase efficacy and lower toxicity.
Our goal is to develop clinically relevant approaches that will improve efficacy and safety of hematopoietic stem cell transplantation to treat cancer patients. The fundamental insights gained from these studies will have broad and rapid implications to cancer therapy.
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|Griesenauer, Brad; Paczesny, Sophie (2017) The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases. Front Immunol 8:475|
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