The human T cell response to melanoma antigens.
ABSTRACT The cornerstone of the concept of immunosurveillance in cancer should be the experimental demonstration of immune responses able to alter the course of in vivo spontaneous tumor progression. Elegant genetic manipulation of the mouse immune system has proved this tenet. In parallel, progress in understanding human T cell mediated immunity has allowed to document the existence in cancer patients of naturally acquired T cell responses to molecularly defined tumor antigens. Various attributes of cutaneous melanoma tumors, notably their adaptability to in vitro tissue culture conditions, have contributed to convert this tumor in the prototype for studies of human antitumor immune responses. As a consequence, the first human cytolytic T lymphocyte (CTL)-defined tumor antigen and numerous others have been identified using lymphocyte material from patients bearing this tumor, detailed analyses of specific T cell responses have been reported and a relatively large number of clinical trials of vaccination have been performed in the last 15 years. Thus, the "melanoma model" continues to provide valuable insights to guide the development of clinically effective cancer therapies based on the recruitment of the immune system. This chapter reviews recent knowledge on human CD8 and CD4 T cell responses to melanoma antigens.
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ABSTRACT: Adoptive immunotherapy with tumor infiltrating lymphocytes (TILs) is a potent ther-apy for metastatic melanoma. In this process, naturally occurring tumor reactive TILs that bear T-cell receptors (TCR) targeted against tumor cells are generated ex vivo and administrated into the patients. The generation of tumor-reactive T cells is not always possible in all of the patients. To overcome this limitation, we can now insert highly avid TCRs into T cells that can recognize tumor antigens. Genetic engineering of TCR genes into normal T cells is a powerful new strategy to generate large numbers of defined antigen-specific cells for therapeutic application. This approach has evolved beyond experimental stage into a clinical reality. The feasibility of TCR-engineered T cells has been shown to be an effective clinical strategy resulting in the regression of established tumors in recent clinical trials. In this review, we discuss the progress and prospects of TCR-engineered T cells as a therapeutic strategy for treating patients with melanoma and other cancers.Gene Therapy and Regulation 10/2010; 1(5):67-80. DOI:10.1142/S1568558610000161
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ABSTRACT: Malignant cells are frequently recognized and destroyed by T cells, hence the development of T cell vaccines against established tumors. The challenge is to induce protective type 1 immune responses, with efficient Th1 and CTL activation, and long-term immunological memory. These goals are similar as in many infectious diseases, where successful immune protection is ideally induced with live vaccines. However, large-scale development of live vaccines is prevented by their very limited availability and vector immunogenicity. Synthetic vaccines have multiple advantages. Each of their components (antigens, adjuvants, delivery systems) contributes specifically to induction and maintenance of T cell responses. Here we summarize current experience with vaccines based on proteins and peptide antigens, and discuss approaches for the molecular characterization of clonotypic T cell responses. With carefully designed step-by-step modifications of innovative vaccine formulations, T cell vaccination can be optimized towards the goal of inducing therapeutic immune responses in humans.Seminars in Immunology 04/2010; 22(3):144-54. DOI:10.1016/j.smim.2010.03.004 · 6.12 Impact Factor
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ABSTRACT: The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T(reg)) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-kappaB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.Oncogene 11/2008; 27(45):5904-12. DOI:10.1038/onc.2008.271 · 8.56 Impact Factor