Project 1: Promoting Graft-versus-Tumor Effects in the Bone Marrow

PROJECT SUMMARY / ABSTRACT – Project 1 The use of non-myeloablative (NMA) conditioning has allowed curative allogeneic stem cell transplantation (alloSCT) of older patients (>60yrs) and those with co-morbidities that would otherwise be ineligible for this approach. The Fred Hutchinson Cancer Research Center and this program grant have pioneered this practice changing approach over the last 20 years and it has been taken up globally. While we have continued to make important improvements in supportive care that minimize graft-versus host disease (GVHD) and infectious mortality, relapse remains a major limitation. This program/project addresses this issue and proposes new approaches that focus on 1) the use of hematopoietic and plasma cell target antibodies radiolabeled with the alpha-emitter astatine-211 (211At) to enhance disease eradication during conditioning and 2) mechanisms to enhance immune-mediated Graft-versus-Leukemia (GVL) in settings where GVHD has been effectively mitigated. We will utilize novel preclinical models of primary acute leukemia and myeloma to study the effects of 211At-antibody conjugates on GVHD and GVL/ Graft-versus-Myeloma (GVM) after alloSCT. Subsequently we will test approaches to prevent GVHD that are unlikely to negate GVL, and use this platform to enhance GVL in bone marrow, using clinically tractable checkpoint inhibitors, deletion of suppressive myeloid cells and/or costimulatory agonists. Subsequently we will utilize sophisticated protein and transcriptional based approaches to examine the relationship of T cell function in the peri-transplant period to subsequent survival and disease control in well- annotated clinical cohorts within Projects 2 and 3. A major focus will be the optimization of innovative immunotherapy approaches in preclinical systems for clinical translation.