Use of EGF-R antagonists for the treatment of infections and tumour growth

免疫反应在防止感染和肿瘤生长中起着核心作用。同时，不受控制的免疫反应会造成严重的组织损伤。因此，必须严格调节局部免疫反应，以防止免疫介导的病理。CD4 t细胞的一个子集，被称为调节性t细胞，已被证明是局部免疫调节的重要组成部分。因此，一方面，这些调节性t细胞是确保良好平衡的免疫反应所必需的。另一方面，研究表明，与免疫系统共同进化的病原体和肿瘤已经找到了利用调节性t细胞抑制局部免疫反应并诱导耐受性的方法。因此，在临床环境中，对调节性t细胞功能的靶向干扰可以大大增强感染或癌症患者的病原体/肿瘤特异性免疫反应。不幸的是，人们对炎症部位的调节性t细胞功能的调节知之甚少，因此，在治疗环境中，对特异性干扰调节性t细胞功能的治疗有很高的未满足的医学需求。我们最近发现了一种调控t细胞功能的机制；这是通过生长因子受体EGF-R的表达。这种受体的抑制剂已经在临床上广泛用于治疗某些肿瘤，并且在实验环境中表明，这些抑制剂可以增强病毒感染期间的免疫反应。这些发现表明，这些抑制剂可能至少在一定程度上通过抑制调节性t细胞功能起作用。这种对免疫调节的抑制也可以解释使用EGF-R抑制剂治疗的癌症患者所经历的严重副作用，如皮疹、口炎或腹泻。在本提案中，我们希望证明已经用于临床的EGF-R抑制剂通过抑制体内调节性t细胞的功能来增强抗病毒和抗肿瘤免疫反应。基于这些知识，我们将进一步开发抑制剂，以特异性地干扰调节性t细胞，同时保持这种生长因子受体的其他功能不变。我们希望这种新型抑制剂比当前一代的抑制剂更有效，并且产生更少的副作用，这将允许它们进一步应用于癌症患者，这些患者目前不会考虑用EGF-R抑制剂治疗，或者患有慢性感染的患者。

Immune responses play a central role in the protection against infections and tumor growth. At the same time can uncontrolled immune responses cause severe tissue damage. Local immune responses, therefore, have to be tightly regulated to prevent immune-mediated pathology. A subset of CD4 T-cells, so called regulatory T-cells, has been shown to constitute an important component of local immuno-regulation. Thus, on the one hand these regulatory T-cells are necessary to ensure a well-balanced immune response. On the other hand has it been shown that pathogens and tumours that co-evolved with the immune system have found ways to use regulatory T-cells to dampen local immune responses and to induce tolerance. Thus, translated into a clinical setting, the targeted interference with regulatory T-cell function could substantially enhance the pathogen-/tumor-specific immune response in patients suffering from infections or of cancer.Unfortunately, little is known about the regulation of regulatory T-cell function at the site of inflammation and, as a consequence, there is a high unmet medical need for treatments that specifically could interfere with regulatory T-cell function in a therapeutic setting.We recently discovered a mechanism by which regulatory T-cell function is controlled; which is via the expression of the growth factor receptor, EGF-R. Inhibitors of this receptor are already in wide clinical use for the treatment of some tumours, and in an experimental setting it was shown that these inhibitors enhance immune responses during viral infections. These findings suggest that these inhibitors may function, at least in part, via the suppression of regulatory T-cell function. Such a suppression of immune regulation could also explain for the severe side-effects, such as skin rashes, stomatitis or diarrhea, that are experienced by cancer patients treated with EGF-R inhibitors.In this proposal, we would like to show that EGF-R inhibitors that are already used in the clinic, enhance anti-viral and antitumor immune responses by suppressing the functionality of regulatory T-cells in vivo. Based on that knowledge, we will further develop inhibitors that will interfere with regulatory T-cells specifically, while keeping other functions of this growth factor receptor untouched. We would expect such novel inhibitors to be more effective than the current generation of inhibitors and to induce less side effects, which would allow their further application also in cancer patients that at this moment would not be considered for treatment with EGF-R inhibitors, or in patients suffering from chronic infections.