Project Summary The promise of marrow transplantation (HCT) has been hampered by the threat of relapse, opportunistic infection (OI) and graft-versus host disease (GVHD). These three complications interlock in a Gordian knot that have traditionally precluded independent resolution strategies. In theory, better targeted GVHD prevention would reduce the need for additional immunosuppression (IS) post-HCT, and subsequently lower the rates of OI, as well as of relapse, by conserving the graft-versus tumor (GVT) effect. Transformative advances in the realm of GVHD prevention have been possible due to creative immunomodulatory approaches targeting T-lymphocytes, such as early in-vivo T-cell modulation (post-transplant cyclophosphamide or PTCy based strategies) and co- stimulation blockade of the T-cell and antigen-presenting cell (APC) interaction (Abatacept/Aba). In addition, with a deeper understanding of the role of humoral immunity in chronic GVHD (cGVHD), we and others have shown that B-cell blockade using monoclonal antibodies can be very effective in the prevention and treatment of cGVHD. Hence, we are entering an era in transplantation where we have in a sense, an embarrassment of riches of potential therapeutics, but have yet to establish which of these could be the most effective GVHD prevention strategy, to cut the proverbial Gordian knot, and result in the best patient outcomes. In this project, we focus on the most effective strategy to prevent acute and cGVHD, while maintaining the GVT effect, with acceptable rates of OI. First, we expand on our prior work which has shown that co-stimulation blockade of the CD28/CTLA-4 interaction with Aba (CTLA-4 Ig) results in T-cell inhibition and reduction in aGVHD lethality, first shown in murine and non-human primate models, and then established in early phase and randomized clinical trials. We propose to incorporate Aba with standard of care (SOC) tacrolimus (Tac) and methotrexate (MTX) peri-transplant for reduction of aGVHD. Further, recognizing that does not prevent cGVHD, we seek to develop a cGVHD prevention strategy adjunctive to Aba, leveraging our insights from basic murine and human studies indicating that germinal center formation, the development of autologous and allogeneic antibodies, and B cell cytokines are all important in the generation of cGVHD, This will further expand on our work over the last decade, showing that CD20 targeted monoclonal antibodies (rituximab, Obinutuzumab/Obin) can effectively prevent moderate/severe cGVHD, when given in the first year post-HCT. We propose a 2 arm, phase II randomized trial comparing the combination of Aba/Tac/MTX/Obin (ATOM) with PTCy/Tac/mycophenolate in the myeloablative (MAC) unrelated donor setting (URD) using peripheral blood stem cells (PBSC), to establish the most effective transplant platform to optimize GVHD and non-GVHD outcomes. The intermediate goal is to compare the ability of each therapy to achieve the best GVHD free relapse fre...