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Title	Making T cells more useful: 1) TCR gene transfer 2) Administration of IL-5 following vaccination
Author	Rubinstein, Mark P.
Date	2002
Affiliation/College	College of Graduate Studies
Department	Molecular and Cellular Biology and Pathobiology
Extent	viii, 220 leaves : ill. 29 cm
Source	QW 568 R895m 2002
Subject.MeSH	Academic Dissertations T-Lymphocytes Immunotherapy Neoplasms--therapy Interleukin-15--therapeutic use
Collection	MUSC Theses and Dissertations
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright is held by the author.
Language	English
Type	Text
Format	application/pdf
Media Type	Manuscripts
Resource Identifier	mtd2002_rubinstein_mp
Abstract	Immunotherapy is a promising option in the treatment of a growing number of patients suffering from cancer or infectius disease. This strategy is currently limited though, as success has only been achieved in a small subset of patients. However, as in virtually every type of cancer or infectious disease there is anecdotal evidence of patients spontaneously being cured through immune-mediated mechanisms, there is reason to believe that immunotherapy might be used successfully to treat a larger percentage of patients with otherwise incurable diseases. Taken together with the scientific advances in the past decade, including the sequencing of the human genome and the elucidation of novel immunological pathways, it is quite likely that immunotherapy will in the future make a real beneficial impact on the lives of many people. In this thesis, I detail the work I have done (with the help of many others) to play a small part in contributing to this process. As the field of immunotherapy is broad, in this thesis I have focused on two aspects. First, while there are numerous cell types and effector molecules important in immunotherapy, I focus on T cells. Not because they are more important than other cells and not because they are less so, but because T cells are important. Second, for the majority of this thesis, I focus the discussion on the treatment of cancer, which is a focus of Dr. David J. Cole's laboratory, where I have been fortunate to have the opportunity to do my thesis work. After providing background on immunotherapy, with an emphasis on both T cells and cancer, I will highlight my efforts over the past 7 years in contributing to two projects, both of which involve novel techniques to augment the therapeutic ability of T cells in a manner potentially applicable to cancer therapy. In the first project, we used retroviral vectors to transfer T -cell receptor (TCR) genes and to redirect T cell antigen specificity. On the day I started in the lab there were no reports in the literature of the retrovirally-mediated gene transfer of the genes encoding a complete TCR. Today, there are over a dozen such reports. Our work is the first to show that the transfer of TCR genes can result in the generation of high avidity T cells. High avidity is an important quality as tumor antigens are often only expressed at low levels. In the second project, we evaluated the ability of a recently identified cytokine, IL-15, to act as a vaccine adjuvant. We show for the first time that IL-15 can augment the primary CDS+ T cell response following vaccination. The results from these two projects make important contributions to the development of improved T cell-based therapies. In the last chapter of this thesis, I consider the implications of our findings in cancer therapy. In addition to assessing the potential importance and immediate applications of the individual approaches that we have developed, I discuss the potential value of these approaches in the context of combinatorial therapies. As a rationale for combinatorial therapy, I hypothesize that there may be two key limitations preventing the successful application of T cell-based therapy in most cancer patients: Cancer patients may lack 1) tumor specific T cells and/or 2) an appropriate cellular environment for sustaining a T cell response. As will be discussed, the approaches developed in this thesis directly contribute a mechanism to test this hypothesis, and importantly, a foundation to potentially allow the utilization of immunotherapeutical based therapies in a much wider range of cancer patients.

Making T cells more useful: 1) TCR gene transfer 2) Administration of IL-5 following vaccination

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