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Merchan Lab

Oncolytic Virotherapy; Stromal targeted therapies

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Investigator / Contact Person Jaime Merchan

Research

Dr. Levy has recently made three important discoveries from his ongoing research which have led him to propose clinical studies involving collaborations between UM/UMSCC and industry. First, he published his “2-pathway” strategy to expand Treg cells in vivo (received Till and McCulloch Prize for best basic science paper: Wolf, et. al 2017 BBMT). This demonstrated his ability to manipulate Tregs in vivo using a proprietary fusion protein TL1A-Ig and low dose IL-2. Dr. Levy joined the scientific board of directors of Heat Biologics / Pelican Therapeutics, Inc. an immunotherapy company that has on ongoing gp96 vaccine trial and a strong interest in reagents targeting TNFRSF25. They help support work to assess how the human fusion protein and agonistic mAbs can be used clinically. I have proposed a “pre-clinical” trial in which our in situ expansion strategies will be directly compared to rhuIL-2 for Treg modulation. He proposes to directly compare his 2-pathway TNFRFS25+CD25 strategy versus IL-2 alone in GVHD patients here at UMSCC under the direction of my collaborator, Dr. Komanduri and together with Heat Biologics. This project derives from studies directed supported by the SCC which have resulted in the manuscript noted above, and two other manuscripts (Copsel, et al, BBMT 2018, Wolf JCI Insight, 2018). This work reports the second discovery - directly testing the efficacy of the GVHD prophylactic treatment strategy he developed compared with the current inpatient use of high-dose post-transplant cyclophosphamide (PTCy) regimen. Dr. Levy’s team found that using donor mice who have undergone our 2-pathway donor Treg expansion donor strategy (TrED) vs. PTCy that there are clear benefits to the use of TrED versus PTC based on superior initial lymphoid engraftment.  Dr. Komanduri and Dr. Levy have discussed the notion of a single center trial at UM/SCC using such donors for which they would propose to compare two groups of donors: 1) 1-week low dose IL-2 and 2) two-pathway treated donors for the amelioration of clinical GVHD.   

The lab has also discovered that the absence of the innate immune sensing pathway STING in recipients markedly reduces acute GVHD following allo-HSCT with “MUD” (matched unrelated donors). His student, Cameron Bader received an F31 NCI fellowship, and they generated new collaborations involving SCC (Drs. Roy, El-Rifai, Pillai, Marples) and external scientists (ex. Dr. B. Blazar, U. Minn). They are also evaluating the effect of STING on donor T cell subsets to identify the mechanism to explain the opposing roles of STING in “MUD” vs. MHC-mismatched allo-HSCT. A new exciting thrust has been to implement in vitro organoid cultures. Using specific STING agonists, type I interferons, TNFα and IL-6 - cytokines important in the induction of GVHD are being assessed. They will develop this model: 1) as an approach to assess epithelial, paneth and stem cells in organoid cultures to a) identify which cells produce downstream products of the STING pathway and b) how bacterial vs. DNA contributes to the pathway’s activation and 2) as an approach to methodically assess how conditioning regimens employed for HSCT patients affect STING pathway induction of specific cytokines/chemokine expression. 

They developed the hypothesis that activating the STING pathway together with a tumor vaccine can be optimally exploited in patients undergoing allo-HSCT for hematologic cancers. They have designed experiments to directly test this hypothesis by utilizing our defined GVHD / GVL models to monitor (luciferase imaging) tumor presence in allo-HSCT recipients receiving post-transplant cyclophosphamide.   Dr. Levy’s team reason that following depletion of allo-reactive anti-recipient “GVHD” inducing donor T cells, we can activate STING previously shown via interferon I production to activate APC and promote anti-tumor reactive CD8 T cells. Because of the clinical impact of PTCy for allo-HSCT, this strategy can have a major beneficial impact on the application of tumor vaccines post-HSCT for patients