BM NICHE DISRUPTION AND IMMUNOTHERAPY IN HEMATOLOGICAL MALIGNANCIES

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Abstract Hematopoietic stem cell transplant (HSCT) remains the only curative therapy for many patients with hematologic malignancies and marrow failure states. Key obstacles to the success of HSCT include collecting optimal numbers of hematopoietic stem cells capable of multilineage and durable engraftment, control of graft- versus-host disease (GvHD) and treating disease recurrence both before and especially after HSCT. Dr. DiPersio has focused his career over the last 20 years on overcoming these three obstacles to HSCT through the use of a bench-to-bedside and back again research approach. I have been fortunate to spend my entire 15-year post-graduate research career working with Dr. DiPersio. During this time, I have contributed to 16 of Dr. DiPersio's peer-reviewed manuscripts, completed pre-clinical studies for 4 projects that led to first-in- human clinical trials, assisted in the training of 9 post-docs and/or fellows, trained and supervised 4 technicians and performed correlative studies for 17 different clinical trials involving over 400 patients. Dr. DiPersio's research program over the next several years will use our strengths in preclinical modeling, cancer genomics and the design and execution of early phase clinical trials to 1) develop novel and highly clinically relevant methods to target the hematopoietic niche for optimal mobilization of hematopoietic stem cells and chemo- and nanoparticle-sensitization of acute myeloid leukemia (AML) and multiple myeloma; 2) characterize the genetic and epigenetic changes that contribute to AML relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT); and 3) design and test novel AML immunotherapeutics to reduce the risk of AML relapse before or after HSCT. Successful HSCT requires the infusion of a sufficient number of hematopoietic stem cells that are capable of homing to the bone marrow cavity and regenerating durable trilineage hematopoiesis in a timely fashion. In our first research area, we will use multiple strategies to enhance stem cell mobilization and leukemia chemo- and nanoparticle-sensitization via targeted modulation of the CXCR4/CXCL12, VLA- 4/VCAM-1 and CXCR2/CXCL1-7 axes. In our second major research area we will identify the genetic changes that contribute to AML relapse after alloHSCT in man and mice. Finally, since most patients with AML die from progressive disease after relapse, our third research area will develop and translate into early phase clinical trials novel bi- and tri-specific monoclonal antibody reagents for the treatment of AML relapse before and after HSCT. We will complete a “first-in-man” phase I clinical trial of MGD006, a CD123×CD3 Dual Affinity Re- Targeting (DART) bispecific antibody-based molecule, in patients with relapsed/refractory AML. While this trial is ongoing we are identifying novel targets for immunotherapy in AML and testing the efficacy of new retargeting agents that engage either T cells, NK cells or other immune effector cells to kill AML blasts expressing CD123 or the novel targets. I serve as both a basic researcher and supervisor to accomplish the goals of Dr. DiPersio's cancer research program.