Melanoma vaccines

描述（由申请方提供）：尽管转移性黑色素瘤患者在治疗性疫苗接种后出现临床应答，但仍需改进。已经鉴定了许多潜在的靶抗原，包括共享的肿瘤抗原和给定黑色素瘤特有的“I类”抗原。然而，需要更多地了解如何最好地提供这些抗原，以诱导有效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中治疗有效的肿瘤疫苗，然后将研究结果“翻译”到人类黑色素瘤中，并开发了几种在要求苛刻的小鼠模型中有效的方法。首先，我们表明，转染表达抗CD137 scFv的活的或丝裂霉素C处理的黑色素瘤细胞可以诱导免疫应答，该免疫应答可以消除皮下或肺中生长的已建立的肿瘤。当与相同的小鼠肿瘤相比时，该方法比用表达CD137配体的肿瘤细胞接种或施用抗CD137 MAb更有效。其次，我们证明了转染肿瘤细胞以表达CD83提供了一种增加其免疫原性以用作治疗性疫苗的替代方法。该机制与通过CD 137参与的机制不同，并且这两种方法可以组合以提高疗效。第三，我们有初步的数据表明，转染表达抗CD40 scFv的黑色素瘤细胞在其他两种方法不起作用的模型中作为治疗性疫苗具有功效。基于这些信息，我们现在提出实验来了解更多的机制，并开发基于肿瘤细胞和基因的疫苗，可以治愈具有低免疫原性的黑色素瘤的小鼠。这些发现将被应用于构建人用疫苗，用于体外评价，以确定用于黑素瘤患者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.