The vast majority of T-cells are made in the thymus, a lymphoid organ that is particularly sensitive to radio- or chemotherapy. Strategies to enhance extrathymic T-cell development may therefore be useful to improve the outcome of conditions such as hematopoietic stem cell transplantation, cancer, immunosuppression or certain viral infections. I previously performed studies in mouse models of HSCT and malignancies demonstrating the feasibility and efficacy of adoptive cell therapy with ex vivo generated T cells (preT) to enhance T cell reconstitution. I found that adoptively transferred preT can be used as an "off-the-shelf" cell therapy and administered across MHC barriers to enhance thymic regeneration and T cell immunity. The main goal of this proposal is to develop strategies to enhance thymus independent T cell reconstitution in cancer patients, using tissue culture and tissue engineering based immunotherapeutic approaches. I propose to study the contribution of extrathymic sites to preT- derived T cell reconstitution, and to develop tissue constructs for T cell development ex vivo and in vivo using three-dimensional bioresorbable polymer scaffolds resembling extracellular matrix. Biodegradable polymers have the advantage that they can be used to fabricate micro or nanofibrous three-dimensional matrices for in vivo grafting, and they may be molecularly tailored to release bioactive agents resulting in highly effective localized drug delivery and control of cell growth and differentiation. T cell development will be studied in vitro and in vivo by implanting engineered stromal cell-polymer scaffold composites or cell-free thymic regeneration templates into mice followed by analysis of cell growth, differentiation, migration, and function (including anti-tumor activity). Characterization of host and biomaterial responses will also include analysis of vascularization of implants, biomaterial degradation, and inflammatory responses to implantation. Based on my preliminary data using an improved tissue engineering method with optimized design, biomaterial properties and cell-biomaterial interactions I expect that implantation of a tissue engineered artificial thymic microenvironment will result in enhanced T cell immunity and will contribute to tumor immunosurveillance. My goal over the next five years, with the help of this career development award, is to establish myself as a physician-scientist in the field of Pediatric Hematology/Oncology and to attain a tenure-track position at an academic center. As a physician-scientist, I hope to combine clinical and teaching activities with an independent laboratory-based research program with focus on clinically relevant and translational research.
Cancer patients, in particular those with a high risk of recurrence of their malignancy, receive high doses of chemotherapy and radiation, sometimes followed by transplants of blood or bone marrow stem cells, to replace or fight off diseased cells. However, these high-risk patients often are left vulnerable to life-threatening infections and other complications because along with diseased cells their T cells have been largely wiped out by chemotherapy and radiation. T cells are infection and tumor fighting immune cells and they can take months or even years to become fully functional after cancer treatment and transplantation. T cells develop the thymus, a gland located in the chest where immature blood cells from the bone marrow develop into T (for thymus) cells that are released when they are ready to attack any cells that look foreign. I recently developed a cell culture-based immunotherapy method for the treatment of T cell deficiency in cancer patients and stem cell transplantation recipients. My proposal aims to further explore the potential benefits of immunotherapy with T cell precursors, as well as with tissue engineered T cell development supporting regeneration matrices, to enhance thymus independent T cell reconstitution. Tissue engineering is a field of regenerative medicine aiming at the replacement or regeneration of injured or diseased tissues or organs. In one approach to tissue engineering, a three-dimensional scaffold is constructed in the laboratory simulating the spatial arrangement of cells in the real organ. Scaffolds are filled with microscopic pores where healthy cells are planted. Scaffolds are made from a material that is tolerated by the body's immune system and that gradually degrades inside the body. I propose to apply this tissue engineering principle to the thymus, aiming at the development of an implantable artificial stem cell niche for T cell development. The most immediate application of an artificial thymus is the generation of T cells to enhance immune reconstitution after stem cell transplantation. This strategy may also be of benefit for cancer patients in general by decreasing the risk for infections as well as the progression of cancer cells. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
|Shono, Yusuke; Tuckett, Andrea Z; Liou, Hsiou-Chi et al. (2016) Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-ÎºB-Controlled Oxidative Stress Responses. Cancer Res 76:377-89|
|Tuckett, Andrea Z; Zakrzewski, Johannes L; Li, Duan et al. (2015) Free-hand ultrasound guidance permits safe and efficient minimally invasive intrathymic injections in both young and aged mice. Ultrasound Med Biol 41:1105-11|
|Shono, Yusuke; Tuckett, Andrea Z; Ouk, Samedy et al. (2014) A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. Cancer Discov 4:578-91|
|Tuckett, Andrea Z; Thornton, Raymond H; Shono, Yusuke et al. (2014) Image-guided intrathymic injection of multipotent stem cells supports lifelong T-cell immunity and facilitates targeted immunotherapy. Blood 123:2797-805|
|Velardi, Enrico; Tsai, Jennifer J; Holland, Amanda M et al. (2014) Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med 211:2341-9|
|Zakrzewski, Johannes L; van den Brink, Marcel R M; Hubbell, Jeffrey A (2014) Overcoming immunological barriers in regenerative medicine. Nat Biotechnol 32:786-94|
|Holland, Amanda M; Zakrzewski, Johannes L; Tsai, Jennifer J et al. (2012) Extrathymic development of murine T cells after bone marrow transplantation. J Clin Invest 122:4716-26|