Project 8 - MUC4 Nanovaccine for Pancreatic Cancer

胰腺癌（PC）是一种高转移性和治疗耐药的恶性肿瘤，患者在诊断时出现局部和远处转移。免疫疗法已成为传统疗法的一种可行的替代方案。免疫疗法倾向于通过正确识别肿瘤细胞表面展示的特异性抗原来增强、指导或恢复患者的免疫系统以对抗癌症，从而导致增强的免疫应答。癌症免疫治疗的一个主要挑战是开发疫苗制剂，其可以在面对对肿瘤抗原的免疫耐受时引发细胞介导的免疫应答。寻找适合免疫治疗的新靶点是一个活跃的研究领域。“我们已经证明了MUC 4粘蛋白在PC中过表达。我们小组和其他人的初步研究也证明了MUC 4过表达的癌症患者（胰腺癌和肺癌）中存在循环抗MUC 4抗体。针对MUC 4的体液免疫应答的存在是支持MUC 4在癌症患者中具有免疫原性的事实的证据，并且与该粘蛋白在PC中的过表达一起，支持MUC 4作为有希望的疫苗候选物的情况。这项资助提案的科学依据是评估MUC 4粘蛋白用于胰腺癌免疫治疗的潜力。该提议的总体假设是MUC 4包封到两亲性聚酸酐纳米球中将提供针对PC的上级佐剂性。为了检验这一假设，提出了三个具体目标。目的1：MUC 4纳米疫苗的配制、优化和离体表征。目的2：在胰腺癌的同基因小鼠模型中体内评价MUC 4纳米疫苗。目的3：在MUC 4转基因小鼠模型中评价MUC 4疫苗。我们提出的临床前研究将确定MUC 4是否是疫苗开发的可行靶点。此外，将在MUC 4转基因小鼠中评价MUC 4纳米疫苗，所述MUC 4转基因小鼠与人类情况非常相似，即MUC 4被识别为自身抗原。如果结果令人鼓舞，这种制剂应该准备在未来3-4年内在人类受试者中进行测试。

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.