The genetic introduction of T cell receptor genes into T cells has been developed over the past decade as a strategy to induce defined antigen-specific T cell immunity. With the potential value of TCR gene therapy well-established in murine models and the feasibility of infusion of TCR-modified autologous T cells shown in a first phase I trial, the next key step will be to transform TCR gene transfer from an experimental technique into a robust clinical strategy. In this review, we discuss the different properties of the TCR transgene and transgene cassette that can strongly affect both the efficacy and the safety of TCR gene transfer.
"Beyond the type of vector to be used, it is important to note that as the TCR is a dimer formed of two chains, TCRα and TCRβ, these have to be expressed simultaneously by the engineered cells. As the separate introduction of both chains in the recipient chains has proven difficult and rather ineffective, several vector designs strategies have been elaborated to facilitate the efficient expression of the TCR dimer (reviewed in Uckert and Schumacher, 2009). "
[Show abstract][Hide abstract] ABSTRACT: T-cells are central players in the immune response against both pathogens and cancer. Their specificity is solely dictated by the T-cell receptor (TCR) they clonally express. As such, the genetic modification of T lymphocytes using pathogen- or cancer-specific TCRs represents an appealing strategy to generate a desired immune response from peripheral blood lymphocytes. Moreover, notable objective clinical responses were observed in terminally ill cancer patients treated with TCR-gene modified cells in several clinical trials conducted recently. Nevertheless, several key aspects of this approach are the object of intensive research aimed at improving the reliability and efficacy of this strategy. Herein, we will survey recent studies in the field of TCR-gene transfer dealing with the improvement of this approach and its application for the treatment of malignant, autoimmune, and infectious diseases.
Frontiers in Immunology 07/2012; 3(186):186. DOI:10.3389/fimmu.2012.00186
"using viral or nonviral transduction systems. One strategy uses natural T-cell receptor (TCR) αβ heterodimers of known specificity and affinity for TAAs  . However, it has been argued that formation of chimeric TCRs by pairing of endogenous and transgenic TCR chains may lead to de novo receptor specificities reacting against autologous MHC-peptide complexes and thereby mediate autoimmune reactions. "
[Show abstract][Hide abstract] ABSTRACT: CD4+ and CD8+ T lymphocytes are powerful components of adaptive immunity, which essentially contribute to the elimination of tumors. Due to their cytotoxic capacity, T cells emerged as attractive candidates for specific immunotherapy of cancer. A promising approach is the genetic modification of T cells with chimeric antigen receptors (CARs). First generation CARs consist of a binding moiety specifically recognizing a tumor cell surface antigen and a lymphocyte activating signaling chain. The CAR-mediated recognition induces cytokine production and tumor-directed cytotoxicity of T cells. Second and third generation CARs include signal sequences from various costimulatory molecules resulting in enhanced T-cell persistence and sustained antitumor reaction. Clinical trials revealed that the adoptive transfer of T cells engineered with first generation CARs represents a feasible concept for the induction of clinical responses in some tumor patients. However, further improvement is required, which may be achieved by second or third generation CAR-engrafted T cells.
BioMed Research International 05/2010; 2010:956304. DOI:10.1155/2010/956304 · 2.71 Impact Factor
"Although tumor-infiltrating lymphocytes can be detected in some tumors, their receptors often have a low affinity for TAA, and the generation of tumor-specific T cells from cancer patients is challenging even under the best of conditions (Quintarelli et al., 2008). However, this problem can be overcome by genetically modifying T cells with transgenic αβ T cell receptor chains, which are cloned from high affinity TAA-specific T cell receptors (Uckert and Schumacher, 2009), or by expression of chimeric antigen receptors (CARs) (Dotti et al., 2009), to direct their specificity to tumors. CARs are a fusion of the light and heavy chain variable regions of a monoclonal antibody with the transmembrane and signaling domain of the CD3ζ chain of the T cell receptor and thus, combine the specificity of an antibody with the killing capacity of a T cell. "
[Show abstract][Hide abstract] ABSTRACT: Adoptive transfer of T cells can enhance immune-mediated elimination of tumor cells and provides a specific, non-toxic cancer therapy. This approach has been effective in treating some hematologic and solid malignancies. In addition, the ability to genetically modify T cells to enhance their activity and persistence as well as overcome tumor immune evasion mechanisms has the potential to increase the success of these therapies in a wide range of tumors. In this review we discuss methods for gene transfer and specific modifications that have been made to T cells.
Discovery medicine 04/2010; 9(47):297-303. · 3.63 Impact Factor
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