# Prevention of Graft-Versus-Host-Disease in the Era of Adoptive Immunotherapy

> **NIH NIH P01** · FRED HUTCHINSON CANCER CENTER · 2022 · $885,028

## Abstract

PROJECT SUMMARY/ABSTRACT
Project: Project 3
Allogeneic hematopoietic cell transplantation (HCT) is frequently curative for otherwise fatal leukemia.
However, conventional T cell-replete HCT, using immunosuppressive drugs (IS) alone, is often complicated by
graft-versus-host disease (GVHD), which is associated with mortality in 16% of HCT recipients. Quality-of-life
is compromised by moderate or severe chronic GVHD. Moreover, prolonged GVHD precludes the use of T cell
immunotherapy or vaccination to prevent or treat leukemia that recurs following HCT. T cell depletion is
effective for preventing GVHD, but is complicated by slow immune recovery and high rates of opportunistic
infection. The objective of this project is to develop an improved HCT strategy to prevent GVHD, rapidly
reconstitute pathogen-specific immunity and facilitate future immunotherapeutic approaches to reduce
relapse. The research ultimately aims to improve the health and survival of leukemia patients.
To improve GVHD-free, relapse-free survival (GRFS), we developed two new HCT approaches: 1) peripheral
blood stem cell transplantation (PBSCT) with depletion of naïve T cells from the stem cell graft (TND) and 2)
PBSCT followed by administration of cyclophosphamide 3-4 days after stem cell infusion (post-transplant Cy;
PTCy). In single-arm clinical trials of either TND or PTCy, we observed substantially lower rates of chronic
GVHD than is usual among recipients of PBSCT on conventional HCT plans. We now propose in Aim 1 a
phase II randomized controlled trial (RCT), comparing PBSCT with TND or PTCy to PBSCT with anti-thymocyte
globulin (ATG), the latter a standard GVHD prophylaxis approach, using a flexible, pick-the-winner trial design.
Our goal is to select one novel PBSCT strategy to advance to a phase III RCT that will define the best
approach for maximizing survival while minimizing relapse, GVHD and dependence on IS.
T cell immunotherapy and other immune manipulations delivered in the early post-HCT period have the
potential to reduce relapse and would be enabled by identification of bone marrow lymphocyte signatures that
presage relapse. Exciting new technologies, including single cell RNA sequencing (scRNA-seq) and TCR deep
sequencing (TCR-seq) should facilitate the acquisition of these data and will be evaluated in Aim 2.
The specific aims are:
Aim 1: To conduct a phase II RCT for patients with acute leukemia comparing two novel strategies (TND
and PTCy) to a standard HCT strategy (ATG), aiming to improve GVHD-free, relapse-free survival and
avoid prolonged IS after myeloablative allogeneic PBSCT.
Aim 2: To evaluate reconstitution and function of peripheral blood and bone marrow immune cell
subsets in HCT recipients to determine if lymphocyte signatures are associated with opportunistic
infection or AML relapse.

## Key facts

- **NIH application ID:** 10412941
- **Project number:** 5P01CA018029-47
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Marie Bleakley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $885,028
- **Award type:** 5
- **Project period:** 1997-08-28 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412941

## Citation

> US National Institutes of Health, RePORTER application 10412941, Prevention of Graft-Versus-Host-Disease in the Era of Adoptive Immunotherapy (5P01CA018029-47). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412941. Licensed CC0.

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