Major histocompatibility complex (MHC) class I molecules associate with a variety of peptide ligands during biosynthesis and present these ligands on the cell surface for recognition by cytotoxic T cells. We have designed conditional MHC ligands that form stable complexes with MHC molecules but degrade on command, by exposure to a defined photostimulus. 'Empty MHC molecules' generated in this manner can be loaded with arrays of peptide ligands to determine MHC binding properties and to monitor antigen-specific T-cell responses in a high-throughput manner. We document the value of this approach by identifying cytotoxic T-cell epitopes within the H5N1 influenza A/Vietnam/1194/04 genome.
Adoptive transfer of T-cell receptor (TCR) genes has been proposed as an attractive approach for immunotherapy in cases where the endogenous T-cell repertoire is insufficient. While there are promising data demonstrating the capacity of TCRmodified T cells to react to foreign antigen encounter, the feasibility of targeting tumor-associated self-antigens has not been addressed. Here we demonstrate that T-cell receptor gene transfer allows the induction of defined self-antigenspecific T-cell responses, even when the endogenous T-cell repertoire is nonreactive. Furthermore, we show that adoptive transfer of T-cell receptor genes can be used to induce strong antigen-specific T-cell responsiveness in partially MHCmismatched hosts without detectable graft versus host disease. These results demonstrate the feasibility of using a collection of "off the shelf" T-cell receptor genes to target defined tumor-associated self-antigens and thereby form a clear incentive to test this immunotherapeutic approach in a clinical setting. IntroductionMajor histocompatibility complex (MHC) molecules present peptides on the cell surface irrespective of whether they are derived from foreign proteins or from self-proteins. Different tissue types within the body each express a unique set of proteins, and peptide epitopes derived from such tissue-specific proteins can in principle be used as tumor-rejection antigens. 1 However, because most of these tumor-associated antigens (TAAs) are nonmutated selfantigens, the T-cell repertoire specific for such antigens is generally small in size and low in avidity. Indeed, both preclinical studies and clinical trials have provided evidence that a lack of T cells with the required reactivity is a major factor limiting T-cell-based immunotherapy. For instance, murine studies have demonstrated that tumor-specific T-cell responses against foreign tumor-associated antigens can readily be induced by vaccination. However, when the same tumor-associated antigen is considered "self" by the available T-cell repertoire, reactivity to these antigens is highly reduced. 2,3 In line with this, replacement of the endogenous T-cell compartment through a combination of allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion (DLI) forms an effective treatment strategy for patients with hematologic malignancies such as chronic myeloid leukemia (CML). 4 Importantly, the antileukemic effect of allo-SCT/DLI is dependent on the recognition of minor histocompatibility antigens (MiHAgs) of the recipient as "nonself" by the infused donor lymphocytes, and the development of T-cell responses against such antigens is predictive of remission. 5 The effects of DLI following allo-SCT provide an excellent example of how an endogenous antigen can become foreign by introduction of a novel T-cell compartment and how recognition of endogenous antigens by this exogenous T-cell compartment is associated with remission. The major drawback of this treatment protocol is that the introduced T-cell reactivity against self...
Our results suggest flow cytometric measurement of agonist-induced P-selectin expression can measure PLT quality decline over the entire range encountered during 10-day storage of both standard PLTs and Mirasol-treated PLTs in plasma.
The successful application of T cell-based immunotherapeutic applications depends on the availability of large numbers of T cells with the desired Ag specificity and phenotypic characteristics. Engineering of TCR-transferred T lymphocytes is an attractive strategy to obtain sufficient T cells with an Ag specificity of choice. However, the introduction of additional TCR chains into T cells leads to the generation of T cells with unknown specificity, due to the formation of mixed dimers between the endogenous and introduced TCR chains. The formation of such potentially autoaggressive T cells may be prevented by using γδ T cells as recipient cells, but the in vivo activity of such TCR-engineered γδ T cells has not been established. In the present study, we have investigated the in vivo functionality of TCR-transduced γδ T cells, in particular their Ag specific proliferative capacity, Ag specific reactivity, in vivo persistence, and their capacity to mount recall responses. The results demonstrate that αβ TCR engineering of γδ T cells forms a feasible strategy to generate Ag-specific effector T cells that do not express mixed TCR dimers. In view of increasing concerns on the potential autoimmune consequences of mixed TCR dimer formation, the testing of αβ TCR engineered γδ T cells in clinical trials seems warranted.
Analogous to the clinical use of recombinant high-affinity Abs, transfer of TCR genes may be used to create a T cell compartment specific for self-Ags to which the endogenous T cell repertoire is immune tolerant. In this study, we show in a spontaneous prostate carcinoma model that the combination of vaccination with adoptive transfer of small numbers of T cells that are genetically modified with a tumor-specific TCR results in a marked suppression of tumor development, even though both treatments are by themselves without effect. These results demonstrate the value of TCR gene transfer to target otherwise nonimmunogenic tumor-associated self-Ags provided that adoptive transfer occurs under conditions that allow in vivo expansion of the TCR-modified T cells.
To ensure further clinical development of TCR gene therapy, it is necessary to choose safe T cell target antigens, and implement (combinations of) strategies that enhance the correct pairing of TCR transgenes and the functional avidity and persistence of T cells.
Adoptive transfer of antigen-specific T cells is an attractive means to provide cancer patients with immune cells of a desired specificity and the efficacy of such adoptive transfers has been demonstrated in several clinical trials. Because the T cell receptor is the single specificity-determining molecule in T cell function, adoptive transfer of TCR genes into patient T cells may be used as an alternative approach for the transfer of tumor-specific T cell immunity. On theoretical grounds, TCR gene therapy has two substantial advantages over conventional cellular transfer, as it can circumvent the demanding process of in vitro generation of large numbers of specific immune cells and it allows the use of a set of particularly effective TCR genes in large patient groups. Conversely, TCR gene therapy may be associated with a number of specific problems that are not confronted during classical cellular therapy. Here we review our current understanding of the potential and possible problems of TCR gene therapy, as based on in vitro experiments and mouse model systems. Furthermore, we discuss the prospects of clinical application of this gene therapy approach, and the possible barriers on the route towards clinical use.
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