Regulatory T cells (Tregs) contribute to the maintenance of self-tolerance and mitigate graft-versus-host disease (GvHD), a major complication of allogeneic hematopoietic stem cell transplantation (HSCT), while preserving the beneficial graft-versus-leukemia (GvL) effect. However, in vitro expansion of the rare Treg cell subset is inefficient, costly, and time-consuming. The locus of Foxp3, the master regulator of Tregs, is unmethylated and expressed only in Tregs. We have recently reported that the hypomethylating agent azacitidine (AzaC) induces Foxp3 expression and increases Tregs in vivo, thereby mitigating GvHD without abrogating GvL in a murine allogeneic transplant model. We have also developed an in vivo imaging technique, [18FJ-FHBG-PET, to track genetically-modified T cells carrying a chimeric suicide gene (CD34- TK75). In this renewal, we will further define the optimal conditions for AzaC-induced immune suppression in murine allogeneic transplant models (Aimi), confirm that similar effects can be demonstrated in human T cells using informative xenograft GvHD/leukemia models developed in our lab (Aim 2), and validate the effects of AzaC in a pilot clinical trial (Aim 3). In the clinical trial proposed in Aim 3, we propose to give patients with relapsed AML or MDS after HSCT a donor lymphocyte infusion containing T cells that are transduced with our CD34-TK75 suicide/imaging gene;half will be treated with AzaC. Our hypothesis is that AzaC will convert the T cells into FoxP3+ Tregs that will control the alloreactive T cells thus mitigating GvHD without abrogating GvL effects. The ability of non-invasive [18F]-FHBG-PET imaging to measure the reconstitution, expansion and persistence of adoptively transferred CD34-TK75+ tracer T cells in patients may have significant clinical utility for providing early predictions of GvHD and AzaC treatment efficacy.
If successful, the observation of a "GvHD profile" by [18FJ-FHBG-PET imaging would herald the onset of severe GvHD and the need for initiation of GvHD prophylaxis. In contrast, observation of a "No GvHD" profile would predict negligible to limited GvHD and permit the continued observation of recipients without immunosuppressive medications, thereby permitting a more sustained GvL effect.
|Black, Kvar C L; Akers, Walter J; Sudlow, Gail et al. (2015) Dual-radiolabeled nanoparticle SPECT probes for bioimaging. Nanoscale 7:440-4|
|Kocher, Brandon A; White, Lynn S; Piwnica-Worms, David (2015) DAPK3 suppresses acini morphogenesis and is required for mouse development. Mol Cancer Res 13:358-67|
|Alspach, Elise; Flanagan, Kevin C; Luo, Xianmin et al. (2014) p38MAPK plays a crucial role in stromal-mediated tumorigenesis. Cancer Discov 4:716-29|
|Nickless, Andrew; Jackson, Erin; Marasa, Jayne et al. (2014) Intracellular calcium regulates nonsense-mediated mRNA decay. Nat Med 20:961-6|
|Choi, Jaebok; Cooper, Matthew L; Alahmari, Bader et al. (2014) Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect. PLoS One 9:e109799|
|Garg, Gunjal; Gibbs, Jesse; Belt, Brian et al. (2014) Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3. BMC Cancer 14:35|
|Hensley, Harvey; Devarajan, Karthik; Johnson, James R et al. (2014) Evaluating new therapies in gastrointestinal stromal tumor using in vivo molecular optical imaging. Cancer Biol Ther 15:911-8|
|Garg, Gunjal; Vangveravong, Suwanna; Zeng, Chenbo et al. (2014) Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer. Mol Cancer 13:50|
|Rauch, Daniel A; Harding, John C; Ratner, Lee (2014) IL-15 deficient tax mice reveal a role for IL-1? in tumor immunity. PLoS One 9:e85028|
|Elhammali, Adnan; Ippolito, Joseph E; Collins, Lynne et al. (2014) A high-throughput fluorimetric assay for 2-hydroxyglutarate identifies Zaprinast as a glutaminase inhibitor. Cancer Discov 4:828-39|
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