Cancer immunotherapy attempts to harness the immune system, including T cells, to target and eliminate malignant T cells in the host. However, generating efficient tumor immunity presents a major challenge to the scientist. The immune system is unable to recognize the tumor cells. These cells are resistant to T cell attack and grow uncontrolled. Tumor cells have many characteristics that allow them to escape detection by the immune system. The lack of target antigens on their surface, the difficulty of the immune system in overcoming tolerance to self-antigens on the tumor, and the decreased expression of immune recognized antigens by the tumor all contribute to the ineffective targeting of T cells to cancer cells.In bone marrow transplantation therapy for leukemia, tumor cell degradation is increased by the presence of healthy donor T cells able to target and kill remaining tumor cells. This is called a graft-versus-leukemia effect, which helps the patient to go into remission. However, infusion of T cells included in the donor bone marrow graft can also generate complications as a result of graft-versus-host disease.2 In graft-versus-host disease, the T cells from the donor's marrow may identify the patient's normal tissue as foreign, attacking the patient's healthy cells and causing severe side effects for the patient. This shows that T cells can beneficially kill cancer cells but may be dangerous as well.
[...] Expression of PSMA-specific fusion receptor will be directly demonstrated using anti- HIS6 antibodies. Results The goal of the present study is to genetically engineer a novel T cell receptor that is able to deliver a co-stimulatory signal upon interaction with PSMA. A series of receptors that comprise of a PSMA-specific scFv fragment coupled to a signaling element derived from either 4-1BB or DAP10 were successfully generated. After constructing the P-41BBH6 and P-DAP10H6 genes by PCR, the resulting DNA fragments were cloned into the SFG retroviral vector using restriction enzymes BamH1 and Nco1. [...]
[...] This outcome may be avoided through the introduction of a co-stimulatory chimeric antigen receptor as proposed here. Adoptive therapy using autologous T cells that are genetically modified by such chimeric antigen receptors offers the potential benefit of tumor-specific killing, as well as decreased toxicity relative to conventional chemotherapy and adoptive transfer of non-self, or allogeneic, T cells, which can result in graft- versus-host disease.10 Genetic modification of T cells to recognize these cancerous cells enables scientists to generate more specific T cells to clinically relevant numbers and extend their viability.11 The transfer of specific chimeric antigen- recognition receptors into T cells offers great potential to target T cells to any tumor-associated antigen of interest. [...]
[...] The scFv was then fused to sequences for either HIS6 or MYC tags to allow for antibody-mediated recognition of receptor expression, followed by another fusion to the signaling domains of either 4-1BB or DAP10. These fusion receptors are specific for PSMA, a glutamate carboxypeptidase that is expressed on the surface of normal prostate epithelial cells and is over- expressed in the majority of prostate carcinomas. PSMA is also associated with an array of solid tumors, therefore acting as an attractive target for immunotherapy.1 While PSMA is not normally expressed on the surface of B cell tumors, and the laboratory has previously generated a B cell tumor genetically modified to express PSMA. [...]
[...] Nature Medicine March; 9(3):279-86 Teng, M.W.L, et al. Immunotherapy of Cancer Using Systemically Delivered Gene-Modified Human T-lymphocytes. Human Gene Therapy July; 15:698- 708 Gross, G., and A Eshhar. Endowing T cells with antibody specificity using chimeric T cell receptors. FASEB Journal December; 6(15):3370-8. Disis, Mary L. “Immune System and Antigen Recognition.” Tumor Immunology Dawicki, W., Bertram, E.M., Sharpe, A.H., and T.H. Watts. 4-1BB and OX40 Act independently to Facilitate Robust CD8 and CD4 Recall Responses. The Journal of Immunology, 2004; 173: 5944-51. Laderach, D., Movassagh, M., [...]
[...] Discussion The antigen recognition and signaling functions of antigen receptors are mediated by distinct proteins of the antigen receptor complex.5 When T cell receptor molecules recognize antigens, signals are delivered to the T cell by molecules associated with the T cell antigen receptors.6 Effective activation of T cells requires two signals. The first is provided by the T cell receptor, signal 1. The second signal, or co-stimulatory signal, is provided by receptors on the T cells which bind to specific ligands on the surface of antigen presenting cells (APCs) or target cells, signal 2. [...]
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