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

• 批准号: 10203826
• 负责人: Graham Douglas Hogg
• 金额: $ 3.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10203826
• 关键词: Agonist; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Automobile Driving; CD80 gene; CTLA4 gene; Cell Count; Cells; 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; Life; Ligands; Longevity; Lung; Malignant - descriptor; Malignant Neoplasms; Mediating; Metastatic Melanoma; Methods; Molecular; Mutation; Neoplasms; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Physicians; Play; Population; Pre-Clinical Model; Process; Proteins; Radiation; Radiation therapy; Research Personnel; Resistance; Scientist; Shapes; Sum; Survival Rate; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF5 gene; Testing; Therapeutic; Translating; Translational Research; Translations; Treatment Protocols; Tumor Antigens; Tumor Immunity; Tumor-infiltrating immune cells; Up-Regulation; anti-CTLA4; anti-PD-1; arm; bench to bedside; 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; skills training; success; targeted treatment; therapy resistant; tool; training opportunity; tumor; tumor microenvironment; tumor-immune system interactions

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.

项目总结/摘要 检查点疗法如aPD-1和aCTLA-4代表了癌症疗法的范式转变。他们的成功 在以前的终端诊断，如转移性黑色素瘤，提示两个结论1），免疫 免疫系统是机体防御肿瘤形成的组成要素，以及2）免疫系统是机体防御肿瘤形成的组成要素。 有针对性的工具来治疗疾病。然而，检查点治疗的成功并没有转化为胰腺癌。 导管腺癌（PDAC），这仍然是一种致命的疾病，只有不到10%的患者存活 5年以上9.这种对检查点疗法的抵抗可以部分解释为缺乏常规治疗。 PDAC肿瘤微环境（TME）内的树突状细胞（cDC）。cDC专门用于 引发抗肿瘤T细胞应答，扩增作为靶点的细胞毒性T淋巴细胞（CTL）群体， 比如aPD-1。为了对抗cDC中的这种缺陷，我们采用了一种新的治疗策略， 扩增cDC数量的cDC分化因子Flt 3L，以及针对CD 40的激动性抗体（aCD 40） 许可cDC，增强其癌症抗原呈递能力。令人惊讶的是，这种双重疗法 与单独的单一疗法相比，产生肿瘤内cDC和T细胞的协同增加。 此外，这种组合导致疾病稳定和对放射治疗的重新响应。 这些有希望的观察缺乏一个机制的解释，因为任何一种药物单独的作用方法都是如此。 不能证明它们的组合表型。通过这一提议，我的目标是阐明潜在的细胞途径， PDAC TME内cDC和T细胞数量增加，主要介导aCD 40的功效 + PDAC中的Flt 3L。我假设aCD 40 + Flt 3L的协同益处是通过增强的免疫应答介导的。 将cDC募集到PDAC微环境中，使得能够进行有效的下游引发， 动员肿瘤特异性T细胞应答。初步数据显示，扩大的肿瘤池 浸润性CTL呈现耗竭样特征，表明aCD 40 + Flt 3L双重治疗可使 PDAC对检查点治疗敏感。阐明推动aCD 40+结局改善的机制 Flt 3L治疗的PDAC将有助于优化未来的治疗方案，并促进这种疗法向临床的转化。 这些建议的目标与我个人的目标高度一致，即成为一名专门从事医学研究的物理学家和科学家。 免疫肿瘤学我相信，这份建议书将为我提供所需的技能和经验， 作为一名独立的研究者，我成功地将我实验室的新兴免疫疗法带给了患者 患有恶性肿瘤