Targeting alloantigen presentation in bone marrow to enhance graft-versus-leukemia effects

ABSTRACT Blood cancers account for approximately 10% of all malignancies and allogeneic bone marrow transplantation (BMT) is a preferred curative therapy for these serious conditions. While the therapeutic potential of this procedure lies in graft-versus-leukemia (GVL) effects in which donor T and NK cells eradicate host malignancy, BMT outcomes are limited by transplant-related complications, mainly graft-versus-host disease (GVHD) in which donor T cells attack host normal tissues and opportunistic infections. Indeed, 15-20% of BMT patients develop severe GVHD that is fatal, particularly when involving the gastrointestinal tract, however, relapse of the primary malignancy is still high and eventually responsible for the majority (40-60%) of transplant failures and death. Current prevention and treatment of GVHD which rely on the broad suppression of T cells abate GVL effects. Thus, the immunological intervention to minimize GVHD with promoting GVL is unmet need in BMT. The initiation and maintenance of donor T cell responses are dependent on alloantigen presentation by antigen- presenting cells (APC). Although recently the types of APC that induce and enhance GVHD and the immunological mechanisms therein have been elucidated, their role in GVL and the presence of GVL-specific APC remain unknown. In this proposal, we focus on GVL-requiring APC to enhance GVL and precent leukemia relapse. In particular, we will build on our preliminary data to test the hypothesis that donor T cells primed at extramedullary sites migrate into the BM where their anti-leukemic capacity is maintained via alloantigen presentation by recipient stromal APC. We will utilize cutting-edge mechanistic preclinical murine studies, using advanced flow cytometry, multiplexed immunofluorescence microscopy, RNASeq, and REAP/CITE-seq, to understand antigen presentation required for effective GVL and relapse prevention. Finally, we will test a novel attenuated synthetic IL-18 resistant to the IL-18 binding protein (decoy resistant (DR-18)) that has been fused to CXCR4 nanobody or CD117 antibody to selectively enhance IFNg and antigen presentation locally in the bone marrow. The proposal will lead to a new, clinically tractable approach to selectively promote GVL and prevent relapse after allogeneic BMT.