Altering the specificity of T cell receptor (TCR) is one of the popular strategies to genetically modify T cells for enhancing their tumor-killing activity. Creative Biolabs offers TCR-modified T cells construction services covering every unit, from epitope identification, TCR engineering to a series of validation assays.
T cells play a critical role in immunologic process. Hence, it is important to generate sufficient reactive T cells in the immunotherapies of many diseases. During cancer progression, immune system especially tumor-specific T cells may fail to eliminate cancer because of diverse reasons. The first class is intrinsic immune failure: (1) Tumor-specific T cells might be absent from the immune repertoire. The immune system is sculpted by the mechanisms of central and peripheral tolerance which make tumor-reactive T cells eliminated or only leave weakly tumor-reactive T cells. (2) Antigen-presenting cells (APCs) fail to present tumor-associated antigens in a form that is sufficiently antigenic for T cells, resulting in T cells can`t proliferate and persist in response to tumors. (3) Tumor-reactive immune cells do not localize to the tumor. (4) Regulatory T cells (CD4+CD25+FoxP3+) inhibit tumor-specific T-cell activity. Extrinsic immune evasion is another reason that is responsible for the failure of immune system to eliminate cancer. Tumors undergo a process of immunoediting during their development and growth. (1) Antigens, the peptide itself or combined with MHC molecules, might be down-regulated under immune-selection pressure. (2) Tumor cells or stromal elements can secret various factors to inhibit immune cells or bias the effector type produced. (3) Death-receptor pathways are down-regulated. Death receptors or their downstream signaling molecules might be mutated or lost entirely. So in order to induce effective immune responses, the effective immune response of specific T cells is the most important issue. There are two classical approaches to manipulate T-cell specificity: modification using TCR genes or modification using antibody genes. The former method usually refers to TCR-modified T cells. While the latter method utilizes genes encoding monoclonal antibody chains specific to tumor associated antigens. During the past decades, the strategy to modify T cells through altering the specificity of the TCR has made important advances. To construct TCR-modified T cells, genes encoding the α- and β-chains of TCR are isolated from T cells that are reactive to tumors and then transduce T cells or their precursors. Such TCR-modified T cells have been used in clinic and shown reactivity to tumor cells in vitro, induce antitumor effects in vivo. Based on the factors mentioned above, the T-cell genetic-modification strategies have also been expanded: tranducing T cells with a gene encoding a chimeric receptor that contains co-stimulatory domains; genes encoding growth factos, genes encoding chemokine receptors, suicide genes; transducing heamatopoietic stem cells with TCRs; infecting T cells with retrovirus; using dual-specific T cells; using T cells as APCs; using anti-apoptotic strategies; transducing T cells with; inducing resistance to tumor-derived inhibitory factors, etc.
With advanced technologies and qualified groups, we can provide services for every client seeking for high-quality and cost-effective TCR-modified T cells solution for the scientific research. Our project manager teams can design and perform TCR-modified T cells construction to meet your request.
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