# Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies

> **NIH NIH R35** · WASHINGTON UNIVERSITY · 2021 · $914,570

## Abstract

PROJECT SUMMARY/ABSTRACT
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 (IFNγR) 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 IFNγR, 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...

## Key facts

- **NIH application ID:** 10246817
- **Project number:** 5R35CA210084-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** John F. Dipersio
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $914,570
- **Award type:** 5
- **Project period:** 2017-09-07 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246817

## Citation

> US National Institutes of Health, RePORTER application 10246817, Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies (5R35CA210084-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246817. Licensed CC0.

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