Hematopoietic cell transplantation (HCT) is commonly used to treat blood cancers and is being extensively explored for the treatment of other cancers and blood-related diseases. Unfortunately, a major and potentially life-threatening complication of HCT is graft-versus-host disease (GVHD). GVHD arises when cells in the donor graft recognize the patient's host cells as foreign and attack them, ultimately causing extensive organ damage. It is well known that alloreactive T cells within the graft are responsible for this immunological reaction. Unfortunately, GVHD is often diagnosed when the disease has progressed to a point where current treatments are less effective. More sensitive ways to diagnose GVHD during early disease stages and to monitor treatment response are urgently needed but entirely lacking. In the outlined research we propose to develop such a strategy. Molecular imaging is an exciting new field allowing one to develop imaging technologies that can safely visualize specific cells, even T cells, within a living subject. Specifically, the goal of our proposal is to develop a positron emission tomography (PET) imaging method that can be used to image activated T cells in GVHD. To align with this goal, we have recently developed the novel Fluorine-18 PET tracer 2'-deoxy-2'-[18F]fluoro-9-?- D-arabinofuranosyl guanine ([18F]F-D-AraG), based on a drug called AraG that is known to be selectively cytotoxic towards T cells. Our initial findings with this tracer have shown similar mechanism(s) of uptake as AraG and preferential accumulation in activated T cells. We have also shown the ability to use [18F]F-D-AraG PET imaging to quantitatively visualize locations of T cell accumulation during late-stage GVHD in a mouse model. Here we propose to develop a novel L form of the tracer and compare both the D and L tracers for the ability to accumulate in activated T cells in cell culture and GVHD mice, to optimize the imaging of T cells in GVHD mice and evaluate the ability to detect GVHD prior to clinical symptoms, and to monitor GVHD treatment response in this model. Importantly, these studies will lay the foundation for future evaluation of our tracer in patients with GVHD. The ultimate goal of this technology is to diagnose GVHD at its earliest stages to allow treatments to be applied in a timely manner, to monitor treatment efficacy, and to hopefully improve the outcome of patient's afflicted with this terrible disease.
In this research we are developing a new approach to help battle a devastating transplantation complication called graft-versus-host disease. We propose to develop a new imaging test that can be used to visualize the immune cells responsible for this disease in hopes to allow earlier disease detection to permit more timely treatments that can improve patient outcomes.
|Alam, Israt S; Mayer, Aaron T; Sagiv-Barfi, Idit et al. (2018) Imaging activated T cells predicts response to cancer vaccines. J Clin Invest 128:2569-2580|
|Ronald, John A; Kim, Byung-Su; Gowrishankar, Gayatri et al. (2017) A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant. Cancer Res 77:2893-2902|