http://repub.eur.nl/res/aut/41204/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37355/ 2012-10-03T00:00:00Z During the past few decades great progress has been made in the field of cancer immune therapy. There has been increased understanding on strategies tumors use to induce immune tolerance and evade immune responses, which enabled the design of clinical immune therapy trials. Two recent approaches that either oppose or circumvent immune tolerance towards tumors have successfully been tested in phase I clinical trials. First, immune tolerance can be opposed by monoclonal antibodies that block T cell inhibitory molecules. For example, Ipilimumab and MDX-1106 block Cytotoxic T-Lymphocyte Antigen- 4 (CTLA-4) and Programmed Death-1 (PD-1) receptor, respectively, and administration of these antibodies resulted in anti-tumor activities in patients with metastatic melanoma and renal cell carcinoma. In fact, the combination of Ipilimumab and Dacarbazine (DTIC, currently the standard first-line treatment for melanoma) increased the response rates by three-fold. These results have encouraged further testing of dosing and combinations of these immune modulating reagents. Second, immune tolerance can be circumvented by adoptive transfer of autologous and ex-vivo expanded tumor infiltrating lymphocytes (TILs). TIL therapy preceded by non-myeloablative lymphodepletion resulted in objective response rates in about 50% of advanced metastatic melanoma patients in two different medical centers, suggesting, but not yet proving anti-melanoma activity. Equally interesting were the complete responses observed in TIL therapy that ranged between 10 and 22% and seem higher than those observed for other treatments of melanoma (see Table 1). Recently, a simpler and faster method was developed to generate ‘young’ TILs that harbor characteristics associated with improved T cell persistence and in vivo survival. This young TIL culture protocol yields bulk T cells, omits the extensive in vitro testing of tumor reactivity, enriches for CD8+ T cells and depletes suppressive T cells (Treg cells). Next to TILs, adoptive transfer of tumor specific T cell clones generated from autologous peripheral T cells resulted in objective responses in 8 out of 10 metastatic melanoma patients. Notably, Butler and colleagues ‘educated’ peripheral T cells using artificial antigen-presenting cells loaded with HLA-A2-restricted tumor antigens. This protocol yielded tumor-specific T cells that are clinically long-lived and effective in melanoma patients. Collectively, the above-mentioned studies show the potential of immune therapy and especially the successes of adoptive therapy with tumor-specific T cells. http://repub.eur.nl/res/pub/28455/ 2010-04-01T00:00:00Z Importance of the field: Adoptive T cell therapy (ACT) with tumour infiltrating lymphocytes is currently the best treatment option for metastatic melanoma. Despite its clinical successes, ACT has limitations in availability and generation of therapeutic T cells for a larger group of patients. Introduction of tumour-specific T cell receptors into T cells, termed TCR gene therapy, can provide an alternative for ACT that is more widely applicable and might be extended to other types of cancer. Areas covered in this review: The current status of TCR gene therapy studies including clinical challenges, such as on-target toxicity, compromised anti-tumour T cell responses, compromised T cell persistence and potential immunogenicity of receptor transgenes. Strategies to address these challenges are covered. What the reader will gain: A listing and discussion of strategies that aim at improving the efficacy and safety of TCR gene therapy. Such strategies address antigen choice, TCR mis-pairing, functional avidity and persistence of T cells, immune responses towards receptor transgenes, and combination of ACT with other therapies. Take home message: 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.