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T cells engineered with a T cell receptor against the prostate antigen TARP specifically kill HLA-A2+ prostate and breast cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 39, 15877-15881 p.Article in journal (Refereed) Published
Abstract [en]

To produce genetically engineered T cells directed against prostate and breast cancer cells, we have cloned the T-cell receptor recognizing the HLA-A2–restricted T-cell recptor γ-chain alternate reading-frame protein (TARP)4–13 epitope. TARP is a protein exclusively expressed in normal prostate epithelium and in adenocarcinomas of the prostate and breast. Peripheral blood T cells transduced with a lentiviral vector encoding the TARP-TCR proliferated well when exposed to peptide-specific stimuli. These cells exerted peptide-specific IFN-γ production and cytotoxic activity. Importantly, HLA-A2+ prostate and breast cancer cells expressing TARP were also killed, demonstrating that the TARP4–13 epitope is a physiologically relevant target for T-cell therapy of prostate and breast cancer. In conclusion, we present the cloning of a T cell receptor (TCR) directed against a physiologically relevant HLA-A2 epitope of TARP. To our knowledge this report on engineering of T cells with a TCR directed against an antigen specifically expressed by prostate cells is unique.

Place, publisher, year, edition, pages
2012. Vol. 109, no 39, 15877-15881 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-181199DOI: 10.1073/pnas.1209042109ISI: 000309604500071OAI: oai:DiVA.org:uu-181199DiVA: diva2:553426
Available from: 2012-09-19 Created: 2012-09-19 Last updated: 2017-12-07Bibliographically approved
In thesis
1. The Multiple Faces of Genetically-Modified T Cells: Potential Applications in Therapy
Open this publication in new window or tab >>The Multiple Faces of Genetically-Modified T Cells: Potential Applications in Therapy
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this PhD thesis the potential of T-cells as therapy for disease are explored. The applications of genetically modified T-cells for treatment of cancer and autoimmune disease; the functionality and optimal activation of T-cells are discussed.

Successful treatment of cancer with T-cell receptor (TCR)-modified T-cells was first reported in 2006, and is based on recognition of a specific peptide by the TCR in the context of the MHC molecule. As antigen presentation in tumors is often defective and to avoid MHC-restriction, chimeric antigen receptors (CAR) molecules containing an antibody part for recognition of cell surface antigens and TCR and co-receptor signaling domains have been developed. Activated T-cells mount an efficient immune response resulting in the killing of the cancer cell and initiating T-cell proliferation. The rationale for using genetically modified T-cells instead of isolating tumor infiltrating lymphocytes from the tumor and expanding them (TIL therapy) is that it is often very difficult to obtain viable lymphocytes that are able to expand enough in order to use them for therapy.

This thesis explores the possibility of using prostate-specific antigens to target T-cells towards prostate cancer. The prostate has many unique tissue antigens but most patients with metastatic prostate cancer have undergone prostatectomy and consequently have “prostate antigen” expression only in cancer cells. We targeted the prostate antigens TARP and PSCA with a HLA-A2 restricted TCR and a CAR respectively. In both cases the tumor-specific T-cells were able to generate potent proliferative and cytotoxic responses in vitro. The PSCA CAR-modified T-cells delayed subcutaneous tumor growth in vivo. It is evident from our in vivo experiments that the PSCA CAR T-cells were unable to completely cure the mice. Therefore, we aimed to improve the quality of the transferred T-cells and their resistance to the immunosuppressive tumor microenvironment. Stimulation with allogeneic lymphocyte-licensed DCs improved the resistance to oxidative stress and antitumor activity of the T-cells.

We further investigated the potential of genetically modified regulatory T-cells (Tregs) to suppress effector cells in an antigen-specific manner. Using a strong TCR we hypothesize that the phenotype of the TCR-transduced Tregs may be affected by antigen activation of those cells. We found that the engineered Tregs produced cytokines consistent with Th1, Th2 and Treg phenotypes.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2014. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1032
Keyword
cancer immunotherapy, genetically engineered T cells, chimeric antigen receptor, T cell receptor, antigen-specific T cells, immunotherapy
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Immunology; Clinical Immunology
Identifiers
urn:nbn:se:uu:diva-232850 (URN)978-91-554-9050-8 (ISBN)
Public defence
2014-11-15, Rudbecksalen, Dag Hammarsjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-10-24 Created: 2014-09-25 Last updated: 2015-01-23

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Hillerdal, VictoriaNilsson, BerithEssnd, Magnus

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