Project 4 Program Director (Last, first, m/cWIe): Piwnica-Worms, D.DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness ofthe project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe therationale and techniques you will use to pursue these goals. Patients with leukemia or lymphoproliferative disorders who receive allogeneic stem cell transplantation (SCT), but then later relapse, have only a 50% survival rate. Donor lymphocyte infusions (DLI) have resulted in some cures, but while the donor T cells begin to eradicate the leukemic cells, they can also react againstthe recipient's tissues, causing graft versus host disease (GvHD). The anti-leukemic effect parallels the severity of GvHD, which can be fatal. Thus, the ideal scenario would be to infuse T cells from a matched donor to exert the GvL response, but to eliminate them if GvHD begins to develop. Our funded clinical trial seeks to do that, by transducing the donor T cells with a chimeric CD34-mutant 75 HSV1-Thymidine Kinase (CD34-TK75) suicide gene, prior to infusion into patients who have relapsed hematologic malignancies after allogeneic SCT. The CD34 epitope allows efficient selection of engineered cells and the TK75 protein allowsthe transduced cells to be killed by administration of ganciclovir, a clinically approved drug. There is currently no reliable way to know whether patients will, or will not, develop GvHD following transplantation orDLI, and often the disease is already progressing toward severe organ damage by the time clinical symptoms such as a skin rash occur.
In Specific Aim 1, we propose to imageTK75-transduced T cells in the recipient with positron emission tomography (PET) and the TK substrate, 9-(4-[18FI]-fluoro-3-hydroxymethyl- butyl)guanine ([18F]FHBG). The proposed imaging trial will allow us to define patterns of T cell trafficking in humans post-DLI, that are predictive of GvHD before clinical symptoms occur. Based on our preliminary data, we hypothesize that a robust expansion of donor T cells in the lymph nodes of the patient will precede the onset of severe GvHD, whereas less vigorous expansion and a more diffuse pattern of T cell distributionwill indicate tolerance. Using our recently developed NOD/SCID/p2M-null mouse model of human T cell- induced GvHD, specific aim 2 will test that a portion of the GMP-grade T cell product that was administeredto the patients has retained immunologic function. Frequent microPET imaging and tissue studies will evaluate the severity of GvHD. If our hypothesis is correct, then monitoring patterns of donor T cells by PETimaging would provide a non-invasive molecular marker to guide the timing of therapeutic ganciclovir administration. This novel T cell suicide gene therapy/ DLI / PET imaging study could significantly extend the life expectancy of patients with relapsed leukemia after allogeneic transplantation.
Showing the most recent 10 out of 283 publications
