# Targeting antigen cross-presentation to enhance anti-leukemic responses after allogeneic transplantation

> **NIH NIH K23** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $196,560

## Abstract

PROJECT SUMMARY / ABSTRACT
The central goals of this proposal are a) to support the acquisition of advanced training in clinical research
methodologies, ethical principles and human immunology as it pertains to conducting patient-oriented
investigations in allogeneic hematopoietic stem cell transplantation (HCT) and b) to vigorously pursue a deep
understanding of biology guided proof-of-concept trials in HCT directed at reducing relapse in Acute Myeloid
Leukemia (AML). I will achieve these goals within five years by completing the following career development
activities: 1) serving as a mentored principle investigator on a clinical study directly translated from the
laboratory 2) acquiring in-depth laboratory training in monitoring human allogeneic HCT immune responses
and 3) completing graduate coursework in immunology together with a Master's of Science in Clinical
Research Design and Statistical Analysis (CRDSA).
Allogeneic HCT represents the lone curative approach for several malignant hematologic diseases including
AML. HCT delivers potent immunotherapeutic effects through graft-versus-leukemia (GVL) responses of donor
lymphocytes. Despite this great potential, relapse remains the major impediment to improving survival after
HCT. Reducing relapse by increasing high dose chemotherapy (conditioning) or administration of donor
lymphocytes (DLI) are limited by major toxicity, primarily graft-versus-host disease (GVHD).
Shared immunity against normal and malignant host tissues underlies the difficulty in separating GVL from
GVHD. To overcome this barrier, donor T cells must be `primed' to more specifically respond to leukemia
antigens that are not presented directly but instead presented by the professional antigen presenting cells
(APCs), a process known as cross-presentation. Specialized APCs found in mice (CD8α+ DCs) and their
counterparts in humans (BDCA3+ DCs), are crucial for initiating leukemia antigen specific T cell responses. In
preclinical studies of HCT, we demonstrate enhancing cross-presentation on CD8α+DCs promotes GVL
responses without aggravating GVHD. Moreover, type 1 interferon (IFN-α) is capable of enhancing cross-
presentation and subsequent GVL in models of HCT. In Specific Aim 1, these concepts are directly translated
to a proof-of-concept phase I/II clinical trial to reduce the recurrence of AML after HCT in patients at high risk
for relapse. We will test the hypothesis that treatment with the FDA approved agent pegylated IFN-α will
reduce relapse without increasing the frequency or severity of GVHD. In Specific Aim 2, we determine the
impact of pegylated IFN-α on cross-presentation of leukemia antigens on BDCA3+ DCs. We will test the
hypothesis that enhancing cross-presentation will result in increases in leukemia antigen specific T cell
responses.
This proposal reflects a logical extension of my prior research and follows a well laid out plan for career
development. It is the first HCT study specifically designed to targ...

## Key facts

- **NIH application ID:** 9839476
- **Project number:** 5K23AI123595-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** John Martin Magenau
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,560
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839476

## Citation

> US National Institutes of Health, RePORTER application 9839476, Targeting antigen cross-presentation to enhance anti-leukemic responses after allogeneic transplantation (5K23AI123595-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9839476. Licensed CC0.

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