# Targeted manipulation of the DNA damage response for prevention/treatment of GVHD

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $198,750

## Abstract

Graft versus host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic
stem cell transplantation (HSCT). GVHD prophylaxis is commonly based on either calcineurin
inhibitors or post-transplant cyclophosphamide (PTCy). PTCy is increasingly employed for
prevention of GVHD with improved overall outcomes. However, GVHD continues to be a
significant problem and conventional chemotherapeutic toxicities of PTCy remain a concern.
We have recently found that activated T cells display very strong DNA damage response (DDR)
markers, and that small molecule-mediated inhibition of selected proteins in the DDR signaling
cascade constitutes a novel, effective, and low toxicity method for deleting unwanted T cell
responses. We are now seeking to investigate this therapy in allogeneic HSCT and preliminary
studies indicated that combination DDR-based therapy, which we term `cell cycle checkpoint
release' (CCCR) therapy, is highly effective at preventing GVHD in a murine model. Our work
has led to our central hypotheses, that: 1) T cells initiating/ driving GVHD in mice and humans
can be efficiently targeted with CCCR therapy with less off target toxicity than conventional DNA
damaging agents such as cyclophosphamide, and 2) Because of its improved therapeutic index,
episodic CCCR would be effective and tolerable therapy for established GVHD. We propose to
test this hypothesis by first defining the efficacy of CCCR in multiple models as either
prophylaxis or treatment of established GVHD. Next we will closely assess the toxicities of this
approach, in comparison to PTCy. Finally, we will assess cells from patient undergoing HSCT
to look for evidence of ongoing DDR and sensitivity to CCCR in activated T cells associated with
clinical GVHD. Application of targeted DDR-based approaches is ideal for transplantation as the
kinetics of allogeneic rejection/GVHD can be defined in clinical contexts. Successful application
of targeted DDR-based approaches such as CCCR to transplantation would alter clinical
paradigms and improve outcomes for patients undergoing transplantation.

## Key facts

- **NIH application ID:** 9849180
- **Project number:** 5R21AI142266-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Michael Jordan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,750
- **Award type:** 5
- **Project period:** 2019-01-15 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849180

## Citation

> US National Institutes of Health, RePORTER application 9849180, Targeted manipulation of the DNA damage response for prevention/treatment of GVHD (5R21AI142266-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9849180. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*