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Harnessing Dendritic Cells as a Novel Therapy in Pancreatic Ductal Adenocarcinoma

利用树突状细胞作为胰腺导管腺癌的新疗法

基本信息

批准号：
10653174
负责人：
Graham Douglas Hogg
金额：
$ 5.27万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653174
关键词：
Agonist Antibodies Antigen Presentation Antigen-Presenting Cells Automobile Driving CD80 gene CTLA4 gene Cell Count Clinic Clinical Clinical Trials Combination immunotherapy Combined Modality Therapy Cytotoxic T-Lymphocytes Data Dendritic Cells Development Diagnosis Disease Elements FLT3 ligand Frequencies Future Genetic Goals Human Immune Immune Evasion Immune system Immunooncology Immunotherapy Infiltration Licensing Ligands Longevity Malignant - descriptor Malignant Neoplasms Mediating Metastatic Melanoma Methods Molecular Mutation Neoplasms Non-Small-Cell Lung Carcinoma Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Physicians Play Population Pre-Clinical Model Process Proteins Radiation therapy Research Personnel Resistance Scientist Shapes Sum Survival Rate T cell infiltration T cell response T-Lymphocyte T-Lymphocyte Subsets TNFRSF5 gene Testing Therapeutic Training Translating Translational Research Translations Treatment Protocols Tumor Antigens Tumor Escape Tumor Immunity Up-Regulation anti-CTLA4 anti-PD-1 arm bench-to-bedside translation cancer infiltrating T cells cancer therapy career cell transformation checkpoint therapy chemokine combat cytokine density design disorder control exhaust experience human disease improved improved outcome ineffective therapies melanoma morphogens mouse model mutant neoantigens novel novel strategies novel therapeutics pancreatic ductal adenocarcinoma model programmed cell death ligand 1 programmed cell death protein 1 recruit response skills success targeted treatment therapy resistant tool training opportunity translational therapeutics tumor tumor microenvironment tumor-immune system interactions

项目摘要

Project Summary / Abstract Checkpoint therapies such as aPD-1 and aCTLA-4 represent a paradigm shift in cancer therapy. Their success in previously terminal diagnoses such as metastatic melanoma, prompt two conclusions 1) that the immune system is a constitutive element of the body’s defense against neoplasia and 2) that the immune system is a targetable tool to treat disease. However, the successes of checkpoint therapy have not translated to pancreatic ductal adenocarcinoma (PDAC), which remains a deadly disease with fewer than 10% of patients surviving beyond 5 years9. This resistance to checkpoint therapies can be partly explained by a paucity of conventional dendritic cells (cDCs) within the PDAC tumor microenvironment (TME). cDCs are uniquely specialized for priming anti-tumor T cell responses, expanding a population of cytotoxic T lymphocytes (CTLs) that are the target of therapies such as aPD-1. To combat this deficit in cDCs, we have employed a novel strategy of treating with the cDC differentiation factor Flt3L to expand cDC numbers, and an agonistic antibody against CD40 (aCD40) to license cDCs, augmenting their cancer-antigen presentation capacity. Surprisingly, this dual therapy generates a synergistic increase in intra-tumoral cDCs and T cells, compared to either monotherapy alone. Additionally, this combination leads to disease stabilization and renewed responsiveness to radiation therapy. These promising observations lack a mechanistic explanation, as the method of action of either drug alone does not justify their combined phenotype. Through this proposal, I aim to elucidate the cellular pathways underlying the increased numbers of cDCs and T cells within the PDAC TME, which largely mediate the efficacy of aCD40 + Flt3L in PDAC. I hypothesize that the synergistic benefit of aCD40 + Flt3L is mediated through enhanced recruitment of cDCs to the PDAC microenvironment, enabling effective downstream priming and mobilization of a tumor specific T cell response. Preliminary data indicate that the expanded pool of tumor infiltrating CTLs assumes an exhausted-like profile, suggesting that aCD40 + Flt3L dual therapy may render PDAC sensitive to checkpoint therapies. Clarifying the mechanisms driving the improved outcomes in aCD40 + Flt3L treated PDAC, will help optimize future treatment protocols and spur translation of this therapy to the clinic. These proposed aims are highly aligned with my personal goal of becoming a physician-scientist specializing in immuno-oncology. I am confident that this proposal will provide me with the skills and experience needed to succeed as an independent investigator endeavoring to bring emerging immunotherapies from my lab to patients suffering from debilitating malignancies.

项目摘要/摘要