Project 8 - MUC4 Nanovaccine for Pancreatic Cancer

胰腺癌(PC)是一种高度转移性和对治疗耐药的恶性肿瘤，患者在确诊时出现局部和远处转移。免疫疗法已经成为传统疗法的一种可行的替代方案。免疫疗法倾向于增强、引导或恢复患者的免疫系统，通过正确识别肿瘤细胞表面显示的特定抗原来对抗癌症，从而导致增强的免疫反应。面对肿瘤抗原的免疫耐受，肿瘤免疫治疗中的一个主要挑战是疫苗配方的开发，该疫苗配方可以诱导细胞介导的免疫反应。寻找适合免疫治疗的新靶点是一个活跃的研究领域。我们已经证明MUC4粘蛋白在PC中高表达。我们小组和其他人的初步研究也表明，在MUC4过度表达的癌症患者(胰腺癌和肺癌)中存在循环ANFI-MUC4抗体。针对MUC4的体液免疫反应的存在是支持MUC4在癌症患者中具有免疫原性的证据，再加上这种粘蛋白在PC中的过度表达，支持MUC4作为一种有前途的候选疫苗的情况。这项拨款提案的科学基础是评估MUC4粘蛋白用于胰腺癌免疫治疗的潜力。该提议的总体假设是，将MUC4包裹到两亲性聚酸酐纳米球中将提供对PC的优越佐剂能力。为了检验这一假设，本文提出了三个具体目标。目的1：MUC4纳米疫苗的制备、优化及体外特性研究。目的：研究MUC4纳米疫苗在同基因小鼠胰腺癌模型中的体内应用效果。目的3：在MUC4转基因小鼠模型中评价MUC4疫苗。我们提议的临床前研究将确定MUC4是否是疫苗开发的可行靶点。此外，MUC4纳米疫苗将在MUC4转基因小鼠身上进行评估，这与人类的情况非常相似，即MUC4被认为是一种自身抗原。如果结果令人鼓舞，这种配方应该在未来3-4年内准备好在人体上进行测试。

Pancreatic cancer (PC) is a highly metastatic and therapy-resistant malignancy with patients presenting with local and distant metastases at the time of diagnosis. Immunotherapy has emerged as a viable alternative to conventional therapies. Immunotherapy tends to boost, direct, or restore the patient's immune system to fight cancer by proper recognition of specific antigens displayed by tumor cells on their surface, leading to an enhanced immune response. A major challenge in cancer immunotherapy is the development of vaccine formulations that can elicit a cell-mediated immune response in the face of immunological tolerance to the tumor antigen. The quest for new targets suitable for immunotherapy is an active area of research.' We have demonstrated that MUC4 mucin is overexpressed in PC. Preliminary studies from our group and others have also demonstrated the presence of circulating anfi-MUC4 antibodies in cancer patients where MUC4 is overexpressed (pancreatic and lung cancer). The presence of humoral immune response against MUC4 is evidence supporting the fact that MUC4 is immunogenic in cancer patients and together with the overexpression of this mucin in PC, supports the case of MUC4 as a promising vaccine candidate. The scientific rationale of this grant proposal is to evaluate the potential of MUC4 mucin for the immunotherapy of pancreatic cancer. The overall hypothesis of the proposal is that the encapsulation of MUC4 into amphiphilic polyanhydride nanospheres will provide superior adjuvanticity against PC. To test the hypothesis three specific aims are proposed. Aim 1: Formulation, optimization and ex vivo characterization of MUC4 nanovaccine. Aim 2: In vivo evaluation of MUC4 nanovaccine in syngeneic murine model of pancreatic cancer. Aim 3: Evaluation of MUC4 vaccine in MUC4 transgenic mouse model. Our proposed preclinical studies will establish whether MUC4 is a viable target to be pursued for vaccine development. Further, MUC4 nanovaccine will be evaluated in MUC4 transgenic mice which closely resemble the human situation i.e MUC4 is recognized as a self-antigen. If the results are encouraging, such formulations should be ready to be tested in human subjects within the next 3-4 years.