Allogeneic hematopoietic stem cell transplant (allo-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/progenitor cells (HSPCs) capable of multilineage and durable engraftment, control of graft-versus-host disease (GvHD), and treating disease recurrence both before and especially after HSCT. I have focused my 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. My research program over the next seven years will use our strengths in preclinical modeling, cancer genomics and the design and execution of early phase clinical trials to (1) develop novel methods to target the hematopoietic niche for optimal HSPC mobilization and chemosensitization of acute myeloid leukemia (AML), (2) target the interferon gamma receptor (IFN?R) and IL-6R signaling pathways via use of selective and balanced JAK1/2 inhibitors to mitigate GvHD while maintaining graft vs. leukemia (GvL) after allo-HSCT, and (3) design and test novel AML and T cell acute lymphoblastic leukemia (T-ALL) immunotherapeutics. Successful HSCT requires the infusion of a sufficient number of HSPCs 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 new strategies to enhance HSPC mobilization and leukemia chemosensitization via targeted modulation of the CXCR4/CXCL12, VLA-4/VCAM-1 and/or CXCR2/Gro-? axes. Managing the threat of GvHD while maximizing the beneficial GvL effect would broaden the scope and usefulness of allo-HSCT. In our second major research area we will perform preclinical and clinical studies to determine if targeting IFN?R, IL-6R, and/or JAK1/JAK2 can mitigate GvHD while maintaining GvL after T cell replete allo-HSCT. Finally, since many 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 ?first-in-man? phase I clinical trials of MGD006, a CD123xCD3 Dual Affinity Re-Targeting (DART) bispecific antibody-based molecule and AMV564, a CD33xCD3 Tandem Diabody, in patients with relapsed/refractory AML. While these trials are 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, CD33, or the novel targets. Finally, since no targeted therapies currently exist for T-ALL, we are developing allogeneic chimeric antigen receptor T cells (CAR-T) to CD7, a T and NK cell marker that is highly expressed in T cell malignancies and in up to 40% of AML cases. To prevent normal T cell fratricide and alloreactivity, we are using the CRISPR/Cas-9 system to delete CD7 and the TCR? chain from donor T cells prior to transduction with the CD7 CAR.

Public Health Relevance

Allogeneic hematopoietic stem cell transplant (HSCT) is the only curative therapy for many patients with hematologic malignancies and marrow failure states. We will overcome many of the major limitations to successful HSCT by designing and testing in clinical trials our basic science observations which have identified optimal methods of mobilizing stem cells for HSCT and for sensitizing acute myelogenous leukemia (AML) to chemotherapy, by developing and implementing novel methods to prevent graft-versus-host disease (GvHD), the major complication of allogeneic HSCT, and by developing novel immunotherapies for AML and T-ALL.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Unknown (R35)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Song, Min-Kyung H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Khoury, Hanna Jean; Langston, Amelia A; Kota, Vamsi K et al. (2018) Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone Marrow Transplant 53:826-831
Schroeder, Mark A; Choi, Jaebok; Staser, Karl et al. (2018) The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. Biol Blood Marrow Transplant 24:1125-1134
Perry, Justin S A; Russler-Germain, Emilie V; Zhou, You W et al. (2018) CD36 Mediates Cell-Surface Antigens to Promote Thymic Development of the Regulatory T Cell Receptor Repertoire and Allo-tolerance. Immunity 48:923-936.e4
Christopher, Matthew J; Petti, Allegra A; Rettig, Michael P et al. (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N Engl J Med 379:2330-2341
Ghobadi, Armin; Rettig, Michael P; Holt, Matthew S et al. (2018) Ixazomib, an oral proteasome inhibitor, induces rapid mobilization of hematopoietic progenitor cells in mice. Blood 131:2594-2596
Choi, Jaebok; Cooper, Matthew L; Staser, Karl et al. (2018) Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32:2483-2494
Micallef, Ivana N; Stiff, Patrick J; Nademanee, Auayporn P et al. (2018) Plerixafor Plus Granulocyte Colony-Stimulating Factor for Patients with Non-Hodgkin Lymphoma and Multiple Myeloma: Long-Term Follow-Up Report. Biol Blood Marrow Transplant 24:1187-1195
Staser, Karl W; Eades, William; Choi, Jaebok et al. (2018) OMIP-042: 21-color flow cytometry to comprehensively immunophenotype major lymphocyte and myeloid subsets in human peripheral blood. Cytometry A 93:186-189
Cooper, Matthew L; Choi, Jaebok; Staser, Karl et al. (2018) An ""off-the-shelf"" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 32:1970-1983