Melanoma vaccines

描述（由申请人提供）：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，但仍需要改进。许多潜在的靶抗原已经被确定，包括共同的肿瘤抗原和特定黑色素瘤特有的“I类”抗原。然而，如何最好地递送这些抗原，以诱导有效的肿瘤破坏性免疫反应，还需要了解更多。我们的方法是首先构建在小鼠模型中具有治疗效果的肿瘤疫苗，然后将研究结果“转化”到人类黑色素瘤中，并开发了几种在要求高的小鼠模型中有效的方法。首先，我们发现活的或丝裂霉素c处理的黑色素瘤细胞转染表达抗cd137 scFv可以诱导免疫反应，可以消除生长在sc或肺部的肿瘤。当与相同的小鼠肿瘤进行比较时，这种方法比用表达CD137配体的肿瘤细胞接种疫苗或施用抗CD137单抗更有效。其次，我们证明转染表达CD83的肿瘤细胞提供了另一种方法来增加其用作治疗性疫苗的免疫原性。这一机制与CD137不同，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，在其他两种方法无效的模型中，转染表达抗cd40 scFv的黑色素瘤细胞作为治疗性疫苗有效。基于这些信息，我们现在建议进行实验，以更多地了解机制，并开发基于肿瘤细胞和基于基因的疫苗，这些疫苗可以治愈具有低免疫原性的黑色素瘤小鼠。然后，这些发现将用于构建人疫苗进行体外评估，以确定在人类黑色素瘤患者中进行I期试验的疫苗接种策略。虽然我们所有计划的研究都将在黑色素瘤中进行，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.