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 CD123CD3 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.

Public Health Relevance

Hematopoietic stem cell transplant (HSCT) is the only curative therapy for many patients with hematologic malignancies and marrow failure states. Dr. DiPersio's cancer research program seeks to overcome many of the major current limitations to successful HSCT by developing novel methods for mobilizing stem cells for HSCT and for sensitizing leukemia cells to chemo- and nanotherapeutics, identifying the genetic changes that contribute to AML relapse after allogeneic HSCT in man and mice, and by developing novel immunotherapies for AML in an effort to reduce relapse before or after HSCT. I serve as both a basic researcher and supervisor to accomplish the goals of Dr. DiPersio's cancer research program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Project #
5R50CA211466-03
Application #
9547346
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Merritt, William D
Project Start
2016-09-15
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Rettig, Michael P (2018) Get Outta Here! Addition of Mobilizing Agents to Conditioning Regimen Improves Donor Engraftment after Allogeneic Hematopoietic Stem Cell Transplantation for Wiskott-Aldrich Syndrome. Biol Blood Marrow Transplant 24:1309-1311
Ghai, Anchal; Maji, Dolonchampa; Cho, Nicholas et al. (2018) Preclinical Development of CD38-Targeted [89Zr]Zr-DFO-Daratumumab for Imaging Multiple Myeloma. J Nucl Med 59:216-222
Buatois, Vanessa; Johnson, Zoƫ; Salgado-Pires, Susana et al. (2018) Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia. Mol Cancer Ther 17:1739-1751
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
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
Kotagiri, Nalinikanth; Cooper, Matthew L; Rettig, Michael et al. (2018) Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer. Nat Commun 9:275
Schroeder, Mark A; Rettig, Michael P; Lopez, Sandra et al. (2017) Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft. Blood 129:2680-2692
Han, Lina; Jorgensen, Jeffrey L; Brooks, Chris et al. (2017) Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia. Clin Cancer Res 23:3385-3395
Karpova, Darja; Ritchey, Julie K; Holt, Matthew S et al. (2017) Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells. Blood 129:2939-2949

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