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

肿瘤免疫学现在有一个非常坚实的概念基础。挑战仍然是将这些结果转化为临床。人们对癌症疫苗将提供优于传统癌症治疗的优势寄予厚望。疫苗可能比化疗和放疗产生更少和更温和的副作用，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？这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，都是针对肿瘤细胞产生的，导致癌细胞的破坏。这种整合的免疫应答要求疫苗接种策略促进免疫系统的不同细胞之间的最佳串扰。基于使用重组减毒病毒的当前疫苗接种策略未能触发这样的综合应答，因为用当前疫苗接种方案接种的患者的免疫应答比在自然感染期间观察到的那些免疫应答弱几个数量级。优化疫苗接种方案需要更深入地了解免疫系统协调响应病原性感染的信号。因此，模拟这些信号的化合物可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，为免疫治疗提供了一定程度的特异性，这是使用基于活减毒病毒的传统疫苗所不可能实现的。在过去的几年中，我们已经表征了一系列能够激活称为不变NKT细胞的细胞群的合成化合物，其协调专业抗原呈递细胞的成熟（树突细胞）导致杀伤细胞、辅助细胞和抗体产生细胞的活化。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。我们现在非常热衷于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整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.