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: 8719563
• 负责人: Pinku Mukherjee
• 金额: $ 12.8万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719563
• 关键词: Adjuvant; Adjuvant Therapy; Adopted; Adverse effects; Affect; Aftercare; Antibodies; Autoantigens; Binding Sites; Biostatistics Core; Cancer Patient; Cancer Vaccines; Cells; Clinic; Clinical; Clinical Research; Clinical Treatment; Codon Nucleotides; Conjugating Agent; Coxibs; Data; Databases; Development; Diagnostic Neoplasm Staging; Dose; External Beam Radiation Therapy; Funding; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Home environment; Human; Hybridomas; Immune; Immune Targeting; Immune Tolerance; Immune response; Immunosuppressive Agents; KRAS2 gene; Lead; Letters; 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; Pancreatic Ductal Adenocarcinoma; Patients; Peptide Vaccines; Peptides; Phase I Clinical Trials; Recurrence; Resistance; Retrospective Studies; Role; Site; Solid; Specimen; TNFRSF5 gene; Tandem Repeat Sequences; Testing; Therapeutic Intervention; Therapy Clinical Trials; Tissues; Transgenic Mice; Translations; Treatment Protocols; Tryptophan 2,3 Dioxygenase; Tumor Antigens; Tumor stage; Vaccines; base; celecoxib; design; expectation; gemcitabine; human disease; inhibitor/antagonist; innovation; killings; mouse model; novel; outcome forecast; overexpression; pancreatic neoplasm; peptide based vaccine; prevent; response; translational study; tumor; tumor microenvironment; 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靶向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肽结合使用 疫苗和低剂量吉西他滨。 MUC1和KRAS在90％的胰管中表达了 腺癌（PDA），长期以来一直是治疗干预措施的靶标。到目前为止，癌症疫苗 在临床上没有想要的那么成功。疫苗未能产生长期 免疫记忆对肿瘤抗原，因为肿瘤采用了逃避免疫的方法 认可和杀戮。几种可以逆转免疫逃避的新药物已经以适度的测试 临床反应可能是因为这些代理是系统地给药的，并且可能从未 到达肿瘤部位。我们通过将免疫调节剂直接传递到 胰腺肿瘤部位并将其与多肽MUC1/KRAS疫苗结合起来，我们可以产生强大的 抗肿瘤反应具有强烈的记忆响应。治疗将影响本地化和 传播肿瘤和强烈的记忆反应将防止复发。我们将在 适当的自发PDA小鼠模型，与人类疾病明显相似。我们的具体 目的是：1）通过固定四只 通过化学结合肿瘤特异性的化学结合，免疫调节剂直接调节肿瘤部位 MUC1单克隆抗体。该抗体不仅可以回家给主要的胰腺肿瘤，而且还可以回家 超过MUC1的转移性肿瘤部位； 2）评估免疫状态并自然发生MUC1- 胰腺癌患者的特定细胞和体液免疫反应。这个目标将提供坚实的 关于肿瘤相关耐受因子和抗肿瘤反应的作用的数据库 进展，转移，生存和预后以及3）治疗胰腺癌的I期试验。 该试验利用基于MUC1-PEP1IDE的疫苗，Celecoxib，Gemcitabine和外束辐射 局部晚期胰腺癌的患者。我们将监视免疫耐受机制，并 治疗前，期间和之后的免疫反应。未来：这项研究可能导致发展 用于治疗局部和传播胰腺肿瘤的新组合方式。