Monitoring vaccination studies

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Assays to quantitate antigen-specific T cells are crucial for the development of cancer immunotherapy. A major issue in vaccine development is the correlation of clinical efficacy with T cell responses as surrogate markers. There is increasing evidence now from various clinical cancer vaccination trials for a relation between the detection of vaccine-induced T cells by cytokine-based assays and clinical responses (reviewed in 14). Standardization and validation of T cell assays to monitor the induction of specific T cells responses is crucial to reliable monitoring of clinical trials. Several expert workshops have been performed within the EORTC melanoma group and the International Society of Biological Therapy of Cancer (ISBTC) on T cell assay methodology and standardization (15, 16). The simultaneous use of two ex vivo T cell assays including a functional assay for T cell monitoring has been proposed (16). Controls for the quality of the samples as well as for the accuracy and reproducibility of the assay are a prerequiste for clinical T cell monitoring as outlined above.

An effective vaccine should elicit an effector T cell response able to mediate destruction of tumor cells as well as memory T cells providing long-term immunity. Therefore, not only quantitation but also characterization of differentiation subsets of specific T cells is of great interest. A detailed phenotypic analysis of specific T cells is possible by flow cytometric methods. The currently most frequently used classification was proposed by Sallusto et al. based on the expression of the lymph node-homing chemokine CCR7 and CD45RA classifying CD45RA+CCR7+ naive T cells, CD45RA-CCR7+ central memory T cells, CD45RA-CCR7- effector memory T cells and CD45RA+CCR7- effector T cells (17). A similar distinction of T cell subsets can be made using CD27/CD28 (18). These classifications are a very helpful tool to further characterize the type and function of TAA-specific T cell responses and induction of memory as well as effector T cells by peptide vaccination was shown in first studies (19-21). In addition, a number of further characteristics of tumor specific T cells may be important for their efficacy to attack disseminated tumor cells. These include the avidity of the TCR-antigen binding, the presence of cytotoxic granules and the type of cytokine released in response to antigen exposure, the proliferative capacity, and the expression of functional adhesion and chemokine receptors navigating T cells specifically into distinct peripheral tissues. This detailed characterisation will help to understand the nature of vaccine-induced T cell responses in much greater depth and should be valuable for rational and refined clinical development of cancer vaccines.

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