P-4: Direct Delivery of Immune-modulating Therapies to the Pancreatic Tumor Site

P-4：将免疫调节疗法直接递送至胰腺肿瘤部位

• 批准号: 7510798
• 负责人: Pinku Mukherjee
• 金额: $ 30.36万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7510798
• 关键词: Adjuvant; Adjuvant Therapy; Adopted; Adverse effects; Affect; Aftercare; Antibodies; Autoantigens; Binding Sites; Biostatistics Core; Cancer Patient; Cancer Vaccines; Celecoxib/Gemcitabine; Cells; Class; Clinic; Clinical; Clinical Research; Clinical Treatment; Codon Nucleotides; Conjugating Agent; Coxibs; Data; Databases; Development; Diagnostic Neoplasm Staging; Dioxygenases; Dose; External Beam Radiation Therapy; Funding; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Home environment; Human; Hybridomas; Immune; Immune Targeting; Immune Tolerance; Immune response; Immunologic Monitoring; Immunosuppressive Agents; Lead; Letters; Localized; MHC Class I Genes; Malignant Neoplasms; Malignant neoplasm of pancreas; Mayo Clinic Cancer Center; Memory; Modality; Modeling; Monitor; Monoclonal Antibodies; Mucin-1 Staining Method; Mus; Mutate; Neoplasm Metastasis; New Agents; Pan Genus; Pancreatic Ductal Adenocarcinoma; Patients; Peptide Vaccines; Peptides; Phase I Clinical Trials; Protein Overexpression; Recurrence; Resistance; Retrospective Studies; Role; Site; Solid; Specimen; Standards of Weights and Measures; Tandem Repeat Sequences; Testing; Therapeutic Intervention; Therapy Clinical Trials; Tissues; Transgenic Organisms; Translations; Treatment Protocols; Tumor Antigens; Tumor stage; Vaccines; base; design; desire; expectation; gemcitabine; human disease; indoleamine; inhibitor/antagonist; innovation; killings; mouse model; novel; outcome forecast; pancreatic neoplasm; peptide based vaccine; prevent; response; translational study; tumor; tumor progression

Our goal is to target novel immune-modulating agents directly to the pancreatic tumor site using a tumorspecific MUC1 antibody as a carrier. This will be administered in combination with the MUC1/KRAS peptide vaccine and low-dose gemcitabine. MUC1 and Kras are over expressed in 90% of pancreatic ductal adenocarcinomas (PDA) and have long been targets for therapeutic interventions. Thus far, cancer vaccines have not been clinically as successful as one had hoped for. Vaccines have failed to generate long-term immune memory against the tumor antigens because tumors have adopted ways to escape immune recognition and killing. Several new agents that can reverse immune evasion have been tested with modest clinical responses probably because the agents were administered systemically and may have never reached the tumor site. We hypothesize that by directly delivering the immune modulating agents to the pancreatic tumor site and combining this with a multi-peptide MUC1/Kras vaccine, we can generate a robust anti-tumor response with a strong memory response. The treatment will affect both localized and disseminated tumors, and strong memory responses will prevent recurrence. We will test the hypothesis in an appropriate mouse model of spontaneous PDA that clearly resembles the human disease. Our specific aims are: 1) To optimize a MUC1/Kras-based vaccine in the PDA X MUCLTg mice by immobilizing four immune modulating agents directly to the tumor site by chemically conjugating the agents to a tumor-specific MUC1 monoclonal antibody. This antibody will home not only to the primary pancreas tumor but also to the metastatic tumor sites that over express MUC1; 2) To assess immune status and naturally occurring MUC1 - specific cellular and humoral immune responses in pancreatic cancer patients. This aim will provide a solid database as to the roles of tumor-associated tolerizing factors and anti-MUCI responses in tumor progression, metastasis, survival, and prognosis and 3) A Phase I trial for the treatment of pancreas cancer. This trial utilizes a MUC1-pep1ide based vaccine, celecoxib, gemcitabine, and external beam radiation in patients with locally advanced pancreatic cancer. We will monitor the immune tolerance mechanisms, and the immune responses before, during, and after treatment. Future: This study could lead to development of a new combination modality for the treatment of localized and disseminated pancreas tumors.

我们的目标是使用肿瘤特异性药物将新型免疫调节剂直接靶向胰腺肿瘤部位 MUC1抗体作为载体。这将与 MUC1/KRAS 肽联合施用 疫苗和小剂量吉西他滨。 MUC1 和 Kras 在 90% 的胰腺导管中过度表达 腺癌（PDA）长期以来一直是治疗干预的目标。迄今为止，癌症疫苗 临床上并没有像人们希望的那样成功。疫苗未能产生长期效果 针对肿瘤抗原的免疫记忆，因为肿瘤采取了逃避免疫的方式 识别和杀戮。几种可以逆转免疫逃逸的新药物已经过适度的测试 临床反应可能是因为这些药物是系统性施用的并且可能从未有过 到达肿瘤部位。我们假设通过直接将免疫调节剂递送至 胰腺肿瘤位点并将其与多肽 MUC1/Kras 疫苗相结合，我们可以产生强大的 抗肿瘤反应具有强烈的记忆反应。治疗将影响局部和 播散性肿瘤，强烈的记忆反应将防止复发。我们将检验假设 一个合适的自发性 PDA 小鼠模型，与人类疾病明显相似。我们的具体 目标是： 1) 通过固定四只小鼠来优化 PDA X MUCLTg 小鼠中基于 MUC1/Kras 的疫苗 通过将免疫调节剂与肿瘤特异性物质化学结合，将免疫调节剂直接作用于肿瘤部位 MUC1 单克隆抗体。这种抗体不仅会定位于原发性胰腺肿瘤，还会定位于 过度表达 MUC1 的转移性肿瘤部位； 2) 评估免疫状态和自然产生的 MUC1 - 胰腺癌患者的特异性细胞和体液免疫反应。这一目标将为 关于肿瘤相关耐受因子和抗 MUCI 反应在肿瘤中的作用的数据库 进展、转移、生存和预后，以及 3) 治疗胰腺癌的 I 期试验。 该试验使用基于 MUC1-肽的疫苗、塞来昔布、吉西他滨和外照射 局部晚期胰腺癌患者。我们将监测免疫耐受机制，并且 治疗前、治疗期间和治疗后的免疫反应。未来：这项研究可能会导致开发 治疗局限性和播散性胰腺肿瘤的新组合方式。