# The regulation of innate immune sensors to control GVHD and GVL after allogeneic hematopoietic stem cell transplantation

> **NIH NIH F99** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $40,890

## Abstract

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a potentially curative therapy used to treat several
malignant diseases, of which the most frequent is acute myeloid leukemia (AML). As many as half of the ~8,000
aHSCTs performed in the U.S. each year will result in GVHD, thus graft-versus-host disease (GVHD) remains a
significant cause of morbidity and mortality in patients receiving aHSCTs. Pre-transplant conditioning, including
irradiation and chemotherapy for hematological tumors, causes widespread death of dividing cells, release of
endogenous danger signals, and bacterial translocation due to gastrointestinal (GI) epithelial barrier dysfunction.
These events promote the generation of a pro-inflammatory cytokine storm mediated by the activation of innate
immune sensors which drives the differentiation and expansion of allo-reactive donor T cells. Activated donor
anti-host T cells can then damage particular recipient tissues characteristic of GVHD, as well as mediate anti-
tumor immunity targeted to both allogeneic and tumor-antigens. My previous findings demonstrate that
Stimulator of Interferon Genes (STING), an innate immune sensor, promotes inflammation and GVHD following
conditioning and MHC-matched murine aHSCT. The benefit of receiving an aHSCT is the accompanying “graft-
versus-leukemia” (GVL) response, mediated by donor T/NK cells to target and eradicate residual disease.
Therefore, primary objectives of the F99 phase of this proposal are to identify how the STING pathway affects
pre-clinical GVL responses, and if reduced GVHD in the absence of recipient STING can promote tumor
vaccination strategies. Other strategies to reduce inflammatory responses to pre-transplant conditioning include
the development of reduced intensity conditioning (RIC) regimens, which are less toxic than traditional
chemoradiotherapy and lower the risks of both transplant-related mortality and GVHD but are limited in use due
to the significantly increased risk of relapse after RIC. Since the median age of diagnosis for AML - the most
frequent indication for aHSCT - is 68, frailty and the frequency of co-morbidities associated with elevated age
often precludes the use of toxic myeloablative conditioning (MAC) regimens in many aHSCT recipients. As a
result, studies during the K00 phase of this proposal will determine if multiple pre-clinical RIC regimens are
associated with decreased activation of innate immune sensors, reduced GVHD and improved immune
reconstitution after murine aHSCT. Experiments will also determine if prophylactic post-transplant antileukemic
strategies targeting residual AML promotes comparable or improved anti-tumor immunity after RIC versus MAC.
The studies in this proposal will provide new information regarding the involvement of STING and other innate
sensors in the context of aHSCT. The long-term objective of my studies will be to develop new therapies that
can be translated into the clinic to prevent or reduce GVHD without...

## Key facts

- **NIH application ID:** 10014591
- **Project number:** 5F99CA245728-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Cameron Scott Bader
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,890
- **Award type:** 5
- **Project period:** 2019-09-09 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10014591

## Citation

> US National Institutes of Health, RePORTER application 10014591, The regulation of innate immune sensors to control GVHD and GVL after allogeneic hematopoietic stem cell transplantation (5F99CA245728-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10014591. Licensed CC0.

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