A phase I trial in melanoma patients using dendritic cells pulsed with a novel synthetic iNKT cell agonist

肿瘤免疫学现在有了非常坚实的概念基础。挑战仍然是将这些结果转化为临床。人们很期待癌症疫苗能比传统的癌症治疗方法更有优势。与化疗和放疗相比，疫苗可能产生更少、更温和的副作用，因为它们只针对癌细胞。对癌症疫苗的理想免疫反应是什么？整合，意味着免疫系统的所有组成部分，杀伤细胞，辅助细胞和抗体，都被产生以肿瘤细胞为目标，导致癌细胞的破坏。这种综合免疫反应需要疫苗接种策略促进免疫系统不同细胞之间的最佳串扰。目前基于使用重组减毒病毒的疫苗接种策略未能引发这种综合反应，因为采用当前疫苗接种方案接种的患者的免疫反应比自然感染期间观察到的免疫反应弱几个数量级。优化疫苗接种方案需要更深入地了解免疫系统协调对致病性感染作出反应的信号。因此，模拟这些信号的化合物可能被用作当前疫苗接种策略中的佐剂。分子技术的进步已经允许设计亚单位？针对蛋白质靶点的疫苗，提供了一定程度的特异性免疫治疗，这是基于减毒活病毒的传统疫苗所无法做到的。在过去的几年里，我们描述了一系列能够激活一群细胞的合成化合物，这些细胞被称为不变的NKT细胞，它们协调专业抗原呈递细胞（树突状细胞）的成熟，从而激活杀伤细胞、辅助细胞和抗体产生细胞。通过免疫学家、结构生物学家和有机化学家的共同努力，这些研究的结果成为可能。我们现在非常渴望将这些结果转化为临床，以评估在临床前模型中获得的结果是否可以应用于癌症患者，并引发综合的癌症特异性免疫反应。

Tumour immunology is now on a very solid and conceptual footing. The challenge remains to translate these results into the clinic. There is a great expectation that cancer vaccines will offer advantages over conventional cancer treatments . Vaccines are likely to produce fewer and milder side-effects than chemotherapy and radiotherapy as they specifically target cancer cells only. The ideal immune response to a cancer vaccine would be ?integrated , meaning that all components of the immune system, killer cells, helper cells and antibodies, are generated to target tumour cells, leading to the destruction of the cancer cells. Such integrated immune responses require that vaccination strategies facilitate an optimal cross-talk between different cells of the immune system. Current vaccination strategies, based on the use of recombinant attenuated viruses, are failing to trigger such an integrated response, since immune responses in patients vaccinated with current vaccination protocols are orders of magnitudes weaker than those immune responses observed during natural infections. Optimizing vaccination protocols requires a deeper understanding of the signals that the immune system coordinates to respond to pathogenic infection. Compounds that mimic these signals may therefore be exploited as adjuvants in current vaccination strategies. Advances in molecular technology have permitted the design of ?subunit? vaccines directed at protein targets, providing immunotherapy with a degree of specificity that was not possible using traditional vaccines based on live attenuated viruses.Over the last few years we have characterised a series of synthetic compounds capable of activating a population of cells, called invariant NKT cells, which orchestrate the maturation of professional antigen presenting cells (dendritic cells) resulting in the activation of killer cells, helper cells and antibody producing cells. The results of these studies have been possible through a concerted effort between immunologists, structural biologists and organic chemists. We are now very keen to translate these results into the clinic to assess whether the results obtained in pre-clinical models can be applied to cancer patients and trigger an integrated cancer specific immune response.