To improve the immune response to cancer, gene therapy with tumor-specific T cell-receptors (TCRs) provides an attractive approach to effectively arm patients T cells for tumor cell destruction. A high-affinity TCR specific for an antigenic peptide-major histocompatibility complex (pepMHC) can be introduced into patients T cells in vitro, and transfer of transduced T cells could kill cancer cells. The promise of this approach is potentially hindered by mispairing of exogenous TCR chains with endogenous TCR chains that could generate mixed TCR-heterodimers with graft-vs-host specificities. To address the issue of 'mixed' TCR-heterodimers, we investigated the use of single-chain-TCRs (scTv) that lack constant-domains to avoid mispairing and compared activity of T cells expressing scTv relative to full-length TCR in vitro and in a murine tumor model. We demonstrated that the murine scTv m33, specific for a model tumor antigen pepMHC, mediated the activity of both CD4+ and CD8+ T cells with similar sensitivity to full-length m33 TCR. The scTv avoided mispairing with endogenous alpha-beta full-length TCRs and allowed for endogenous TCR surface expression at high levels. In a murine tumor model, CD8+ m33 scTv T cells persisted, whereas CD8+ m33 full-length TCR T cells were deleted, presumably by peripheral tolerance mechanisms.
April 5-6, 2012: Connecting patient care, research, and scientific advancement
This on-campus research symposium aims to bring together members of campus and the surrounding community to foster interdisciplinary discussions on cancer research and its affects on patient care. In order to increase understanding and awareness, we will discuss in an open forum with research talks, poster presentations, and panel discussions. We invite community members, clinicians, and researchers from UIUC and other Midwest regional institutions from departments ranging from the social sciences to basic sciences to engineering and medicine.
The symposium features invited talks from nationally-recognized cancer researchers, oral presentations from UIUC faculty and students, and poster sessions. We encourage student researchers from UIUC and from other regional schools to apply (travel awards are available).
About CC@I Symposium
The Cancer Community at Illinois (CC@I) Symposium is organized by a group of students on the University of Illinois campus to bridge the areas of social science, basic sciences to engineering and medicine as they relate to cancer. The symposium mission is to: 1) Facilitate interdisciplinary collaboration and understanding that transcends established departmental affiliation; 2) Foster an increased understanding of the social and environmental factors affecting patients; and 3) Develop unique vantage points afforded by interactive dialogue between and among the various cancer research disciplines. In order to accomplish this, the symposium will engage the local patient community through use of the nascent social and support efforts of the Mills Breast Cancer Institute, Carle Hospital, and regional clinical collaborators.
Cancerous cells overexpress numerous endogenous proteins that allow for bypass of cell cycle checkpoints and evasion of the immune response. These proteins are cleaved into tumor-associated peptides, expressed on the cell surface of tumor cells in the context of major histocompatibility complex (MHC) proteins, and used as antigens for recognition by T cells. Recently, it has been shown that 87% of breast tumors express the WT-1 Tumor antigen. The identification of specific tumor antigens such as WT-1 presented by tumor cells has increased interest in the development of T cell based therapies. Such approaches include tumor vaccines that elicit T cell responses and antigen specific T cell adoptive therapies. The importance of the T cell response in tumor elimination has been demonstrated through adoptive immunotherapy using T cell clones specific for the MART-1 antigenic peptide in melanoma patients, as well as in an analysis of ovarian carcinomas. Targeting of WT-1 peptides in complex with MHC molecules could allow for similar T cell mediated destruction of cancerous tissue. The binding affinity of T cells specific for cancer antigens is proposed to have a marked affect on T cell mediated cytotoxicity. While T cell therapies have previously been explored, the affect of high affinity TCRs on tumor destruction have not been adequately investigated. High affinity T cell receptors (TCRs) specific to pepMHC complexes have been developed using yeast display technology and have the potential to be used as diagnostic probes for identification of specific antigens on tumor cells, as well as therapeutics through adoptive immunotherapeutic strategies.
The goals of the present work are to engineer a high affinity TCR specific for the clinically relevant tumor antigen WT-1 bound to the class I MHC product HLA.A2 using yeast display, and to express a soluble form of this high affinity TCR in E. coli. Subsequent experiments will explore the activity of single-chain TCRs (scTCRs) as fusions to cytokines for enhanced immune responses.
The prevalence of WT-1 in many human tumors makes it a suitable candidate for the development of a high affinity TCR. Given the undesirable side effects of current cancer therapies, an adoptive immunotherapy utilizing high affinity TCRs provides an attractive alternative to current treatments. High affinity TCRs could provide a tumor specific method to enhance the immune response and eliminate tumors effectively with minimal side effects.
-From David Aggen's Research Synopsis
In collaboration with: Adam S. Chervin, Carolina M. Soto, Thomas M. Schmitt, Boris Engels, Jennifer D. Stone, Sarah A. Richman, Kurt H. Piepenbrink, Brian M. Baker, Philip D. Greenberg, Hans Schreiber, and David M. Kranz
Researchers should cite this work as follows:
David H. Aggen (2012), "[Illinois] Cancer Community Symposium 2012: T Cell Receptors For Potential Cancer Immunotherapy Applications: Single Chain T Cell Receptors Circumvent Mispairing with Endogenous TCR and Mediate T Cell Activity," https://nanohub.org/resources/13951.