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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

基本信息

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
项目类别：
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

项目摘要

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药物直接靶向胰腺肿瘤部位的新型免疫调节剂