Melanoma vaccines

描述(申请人提供)：尽管转移性黑色素瘤患者在治疗性疫苗接种后出现临床反应，但仍有改进的必要。许多潜在的靶抗原已被确定，包括共同的肿瘤抗原和特定黑色素瘤独有的I类抗原。然而，还需要更多地了解如何最好地传递这些抗原来诱导强大的肿瘤破坏性免疫反应。我们的方法是首先构建在小鼠模型上具有治疗效果的肿瘤疫苗，然后将发现“转化”到人类黑色素瘤上，并已经开发出几种方法，对要求苛刻的小鼠模型具有疗效。首先，我们证明了用活的或丝裂霉素C处理的黑色素瘤细胞表达抗CD137单链抗体可以诱导免疫反应，从而消除已建立的生长在皮肤或肺内的肿瘤。与相同的小鼠肿瘤相比，这种方法比用表达CD137配体的肿瘤细胞接种或注射抗CD137单抗更有效。其次，我们证明了通过转染肿瘤细胞表达CD83为提高其作为治疗性疫苗的免疫原性提供了另一种途径。其机制不同于通过CD137参与的机制，这两种方法可以结合使用以提高疗效。第三，我们有初步数据表明，在其他两种方法都不起作用的模型中，转导表达抗CD40单链抗体的黑色素瘤细胞具有作为治疗性疫苗的效果。基于这些信息，我们现在建议进行实验，以了解更多的机制，并开发基于肿瘤细胞和基于基因的疫苗，以治愈免疫原性较低的已建立的黑色素瘤小鼠。然后，这些发现将被应用于构建人类疫苗，用于体外评估，目标是确定人类黑色素瘤患者第一阶段试验的疫苗接种策略。虽然我们计划的所有研究都将针对黑色素瘤进行，但所获得的信息可能也适用于其他肿瘤。

DESCRIPTION (provided by applicant): Although clinical responses in patients with metastatic melanoma occur after therapeutic vaccination, there is a need for improvement. Many potential target antigens have been identified, including shared tumor antigens and "class I" antigens that are unique to a given melanoma. However, more needs to be learned how best to deliver these antigens to induce a potent tumor-destructive immune response. Our approach is to first construct tumor vaccines that are therapeutically effective in mouse models and then to "translate" the findings to human melanoma and have developed several approaches that have efficacy in demanding mouse models. First, we showed that live or Mitomycin C-treated melanoma cells transfected to express anti-CD137 scFv can induce an immune response that can eliminate established tumors growing sc or in the lung. When compared against the same mouse tumors this approach is more effective than vaccination with tumor cells expressing CD137 ligand or administration of anti-CD137 MAb. Second, we demonstrated that transfection of tumor cells to express CD83 provides an alternative way to increase their immunogenicity for use as therapeutic vaccines. The mechanism is different from that engaged via CD137, and the two approaches can be combined for increased efficacy. Third, we have preliminary data indicating that melanoma cells transfected to express anti-CD40 scFv have efficacy as therapeutic vaccines in a model where the two other approaches did not work. Based on this information, we now propose experiments to learn more about mechanisms and to develop both tumor-cell based and gene-based vaccines that can cure mice with established melanomas of low immunogenicity. These findings will then be applied to construct human vaccines for in vitro evaluation towards the goal of identifying a vaccination strategy for Phase I trials in human patients with melanoma. Although all our planned studies will be performed with melanomas, the information gained is likely to be applicable also to other tumors.