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The dual role of complement in both cancer development and treatment has been investigated extensively and is characterized by a substantial literature that documents the conditions in which complement can either enhance tumor growth or promote the killing of malignant cells. Indeed, there are now numerous examples of monoclonal antibodies (mAbs) that have either been approved by the FDA or that are under active investigation that make use of complement when eliminating cancer cells. Although the direct in vitro killing of mAb-opsonized cancer cell lines by complement-dependent cytotoxicity (CDC) can be readily demonstrated, there are considerable challenges related to the translation of these findings to the clinic, and numerous strategies have been employed to maximize mAb-mediated CDC in cancer treatment. These approaches include the redesign of mAb dosing schedules; engineering the Fc regions of the mAbs to enhance complement activation; treatment with cocktails of mAbs that bind to several different sites on the targeted cells and thus that potentially synergize CDC promotion; and neutralizing the complement control proteins on malignant cells to weaken their defenses against complement. Target sites on malignant cells that have been successfully exploited for mAb-induced CDC include CD20, CD37, CD38, CD52, and Epidermal Growth Factor Receptors. MAbs specific to complement components have served as powerful analytical reagents to investigate the detailed mechanisms of CDC, and they have been employed to document complement activation by cancer cells and to examine the role of complement proteins (in particular C1q and fragments of C3 and C5) in supporting tumor growth. The use of polyclonal and mAb reagents has revealed a role for the intracellular complement system in cancer biology and strategies that focus on the interaction of complement with the tumor microenvironment, and examining the impact of the complotype on the response to immunotherapy in cancer should lead to additional mAb-based therapies. Along these lines, there is now increasing evidence that strategies that make use of mAbs or other agents to modulate the action of C3a/C5a or their respective receptors may also find use in cancer immunotherapy.

Cancer --- Cancer vaccines. --- Immunotherapy.

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Cancer vaccines. --- Papillomavirus diseases.

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In zijn oratie belicht Peter Timmerman het vakgebied van therapeutische vaccins, een vrij nieuwe vorm van immuuntherapie die nog in ontwikkeling is, maar mogelijk toepassing gaat vinden voor behandeling van kanker. Therapeutische vaccins activeren het immuunsysteem om antistoffen te maken tegen hormonen die overgereguleerd zijn. Deze hormonen stimuleren tumorgroei. Door ze weg te vangen met behulp van antilichamen kan de tumorgroei afgeremd worden. De werking van therapeutische vaccins lijkt sterk op die van therapeutische antilichamen, die in toenemende mate een vast onderdeel vormen van best

Cancer vaccines. --- Cancer --- Immunotherapy.

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The dual role of complement in both cancer development and treatment has been investigated extensively and is characterized by a substantial literature that documents the conditions in which complement can either enhance tumor growth or promote the killing of malignant cells. Indeed, there are now numerous examples of monoclonal antibodies (mAbs) that have either been approved by the FDA or that are under active investigation that make use of complement when eliminating cancer cells. Although the direct in vitro killing of mAb-opsonized cancer cell lines by complement-dependent cytotoxicity (CDC) can be readily demonstrated, there are considerable challenges related to the translation of these findings to the clinic, and numerous strategies have been employed to maximize mAb-mediated CDC in cancer treatment. These approaches include the redesign of mAb dosing schedules; engineering the Fc regions of the mAbs to enhance complement activation; treatment with cocktails of mAbs that bind to several different sites on the targeted cells and thus that potentially synergize CDC promotion; and neutralizing the complement control proteins on malignant cells to weaken their defenses against complement. Target sites on malignant cells that have been successfully exploited for mAb-induced CDC include CD20, CD37, CD38, CD52, and Epidermal Growth Factor Receptors. MAbs specific to complement components have served as powerful analytical reagents to investigate the detailed mechanisms of CDC, and they have been employed to document complement activation by cancer cells and to examine the role of complement proteins (in particular C1q and fragments of C3 and C5) in supporting tumor growth. The use of polyclonal and mAb reagents has revealed a role for the intracellular complement system in cancer biology and strategies that focus on the interaction of complement with the tumor microenvironment, and examining the impact of the complotype on the response to immunotherapy in cancer should lead to additional mAb-based therapies. Along these lines, there is now increasing evidence that strategies that make use of mAbs or other agents to modulate the action of C3a/C5a or their respective receptors may also find use in cancer immunotherapy.

Cancer --- Cancer vaccines. --- Immunotherapy.

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My work consisted in analysing the frequencies of antitumor CD8 lymphocytes of a melanoma patient who responded to a vaccine made up of Melan-A.A2 and tyrosinase.A2 antigenic peptides. These investigations were carried out using tetramers to analyse specific CD8 lymphocytes directed against antigens of the vaccine, and using MLTC to analyse the other antigens present on the tumor cells. No significant difference between lymphocytes collected before and after vaccination could be found. However the frequency of antitumor CTL others than anti-Melan-A.A2, frequency determined with MLTC, is about 1-350 CD8 lymphocytes. It is probable that this high frequency of anti-Melab-A.A2 CTL of about 1-3.500 lymphocytes CD8 was found using the specific tetramer. Such frequencies of anti-Melan-A.A2 lymphocytes can be observed in melanoma patients and even in healthy individuals. Although the techniques that we used were completely specific, it was impossible to detect, with MLTC or with specific tetramers, amplified T cell clones among the numerous antitumor lymphocytes that were present. We have tried, but without success, to observe an increase in the number of antitumor lymphocytes that carried an activation marker (CD27) or a marker of migration ti the skin (CLA). Finally, many CD8 T cell clones have been obtained from these experiments. Some of them recognize new shared tumor-specific antigens, whose identification is in progress. Le travail entrepris dans ce mémoire consistait à analyser les fréquences des lymphocytes CD8 antitumoraux chez un patient atteint d’un mélanome et ayant répondu à un vaccine constitué des peptides antigéniques Melan-A.A2. Ces investigations ont été réalisées à l’aide de tétramères pour analyser les lymphocytes CD8 spécifiques du vaccin, ainsi que par MLTC afin d’étudier les autres antigènes présents sur les cellules tumorales. A aucun moment, une différence réellement significative entre le nombre de lymphocytes spécifiques issus de prélèvements réalisés avant et après vaccination n’a été mise en évidence. Cependant la fréquence des CTL antitumoraux autres que Melan-A.A2 de 1 sur 3.500 lymphocytes CD8 a été déterminé à l’aide du tétramère spécifique. Une telle fréquence est parfois présente chez des patients atteints d’un mélanome ou même chez des individus sains. Bien que les techniques utilisées soit tout- à fait spécifiques, il est impossible de détecter par MLTC ou analyse à l’aide de tétramères une augmentation d’un ou de plusieurs clones dans la masse énorme des lymphocytes antitumoraux. Nous avons essayé, mais sans succès, de repérer une augmentation de nombre des lymphocytes antitumoraux porteurs d’un marqueur d’activation (CD27) ou d’un marqueur de migration vers la peau (CLA). Enfin, de nombreux clones lymphocytaires T CD8 ont été issus de ces expériences. Certains d’entre eux reconnaissent de nouveaux antigènes tumoraux partagés, antigènes dont l’identification se poursuit.

Killer Cells, Natural --- Melanoma --- Cancer Vaccines