CD40 Pathway in Pancreatic Adenocarcinoma

胰腺癌中的 CD40 通路

基本信息

批准号：
8900213
负责人：
Gregory L Beatty
金额：
$ 16.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8900213
关键词：
Academic Medical Centers Agonist Antigen-Presenting Cells B-Lymphocytes Biometry CD40 Antigens Cancer Control Cell Communication Cells Clinical Clinical Research Clinical Trials Design Cytokine Signaling Cytotoxic Chemotherapy Data Disease Effectiveness Genetically Engineered Mouse Goals Grant Hematology Human Immune response Immunity Immunologic Monitoring Immunologic Surveillance Immunology Immunosuppression Immunosuppressive Agents Immunotherapy Infiltration Inflammation Inflammatory Inflammatory Infiltrate Interleukin-10 Interleukin-6 Ionizing radiation Laboratories Leukocytes Link Malignant Neoplasms Malignant neoplasm of pancreas Mentors Modeling Molecular Monoclonal Antibodies Mus Natural Immunity Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phase Physicians Play Pre-Clinical Model Recruitment Activity Research Resistance Role Scientist Shapes Signal Pathway T cell response T-Lymphocyte TNF gene TNFRSF5 gene Testing Therapeutic Training Tumor Immunity Work antitumor effect career chemotherapy cytokine gemcitabine granulocyte human disease immune activation improved in vivo lymph nodes macrophage mouse model novel novel therapeutics oncology response skills treatment strategy tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): This proposal investigates the CD40 pathway as a key regulator of immune surveillance in a genetically engineered mouse (GEM) model of pancreatic ductal adenocarcinoma (PDA). The candidate is a physician-scientist with training in immunology, hematology, and oncology who is proposing a 5 year mentored research plan with Drs. Carl June and Robert Vonderheide. Formal course work in biostatistics and clinical trial design and interpretation will advance the candidate's skills in interpreting the translational potential of findings obtained in preclinical models. The goal of this career plan is to establish an independent laboratory in an academic department of a university medical center. Research will focus on investigating mechanisms that regulate the capacity of CD40 activation to coordinate productive innate and adaptive anti-tumor immunity. This proposal will use a GEM model of PDA that recapitulates the salient features of human disease. Preliminary data demonstrate that systemic activation of the CD40 pathway can induce tumor regression in pancreatic cancer in mice and humans through a mechanism that is dependent on macrophages but not T cells or chemotherapy. CD40 activated macrophages actively infiltrate the tumor microenvironment, become tumoricidal, and deplete tumor stroma. The recruitment of T cells to the tumor microenvironment is shown to be restrained by IL-10 and the B7-CTLA-4 inhibitory signaling pathway. It is the central hypothesis of this proposal that CD40 plays a critical role in regulating immune surveillance in pancreatic ductal adenocarcinoma through activation of innate immunity but its ability to coordinate productive adaptive anti-tumor immunity is restrained by immunoregulatory pathways controlled by cancer inflammation. To test this hypothesis, three specific aims are proposed. AIM ONE will evaluate the role of leukocytes within the tumor microenvironment in regulating the capacity of CD40- activated macrophages to modulate the tumor microenvironment and induce tumor regression. AIM TWO will examine the role of cytokines in regulating CD40-induced anti-tumor activity. AIM THREE will investigate how cross-talk between antigen presenting cells and T cells regulates the ability of CD40 activation to recruit T cell specific immunity. RELEVANCE: Pancreatic cancer is a devastating disease with few therapeutic options. This proposal will use a mouse model that is indistinguishable from human PDA. Studies in this model will improve the understanding of pathways regulating immune activation within the tumor microenvironment of PDA and may identify novel therapeutic strategies for the treatment of PDA.

描述（由申请人提供）：该提案研究了CD40途径是胰腺导管腺癌（PDA）的基因工程小鼠（GEM）模型中免疫监测的关键调节剂。候选人是一名医生科学家，接受了免疫学，血液学和肿瘤学培训，他建议与DRS一起进行5年的指导研究计划。卡尔·六月和罗伯特·沃德海德。生物统计学和临床试验设计和解释方面的正式课程工作将提高候选人的技能，以解释临床前模型中发现的转化潜力。该职业计划的目的是在大学医学中心的学术部门建立一个独立的实验室。研究将着重研究调节CD40激活能力以协调生产性先天和适应性抗肿瘤免疫力的机制。该建议将使用PDA的宝石模型，该模型概括了人类疾病的显着特征。初步数据表明，CD40途径的全身激活可以通过依赖巨噬细胞而不是T细胞或化学疗法的机制诱导小鼠和人类胰腺癌的肿瘤消退。 CD40激活的巨噬细胞积极浸润肿瘤微环境，变为肿瘤和肿瘤基质。将T细胞募集到肿瘤微环境中被IL-10和B7-CTLA-4抑制信号传导途径限制。这一提案的核心假设是，CD40通过激活先天免疫来调节胰腺导管腺癌的免疫监测至关重要，但通过癌症炎症控制的免疫途径来限制其协调生产性适应性抗肿瘤免疫的能力。为了检验这一假设，提出了三个具体目标。 AIM ONE将评估白细胞在肿瘤微环境中调节CD40活化巨噬细胞调节肿瘤微环境并诱导肿瘤回归的能力的作用。目标两个将检查细胞因子在调节CD40诱导的抗肿瘤活性中的作用。 AIM三将研究抗原呈递细胞和T细胞之间的串扰如何调节CD40激活募集T细胞特异性免疫的能力。相关性：胰腺癌是一种毁灭性疾病，几乎没有治疗选择。该建议将使用与人PDA无法区分的小鼠模型。该模型中的研究将提高对PDA肿瘤微环境中免疫激活的途径的理解，并可能确定用于治疗PDA的新型治疗策略。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial.

DOI：
10.1053/j.gastro.2018.03.029
发表时间：
2018-07
期刊：
Gastroenterology
影响因子：
29.4
作者：
Beatty GL;O'Hara MH;Lacey SF;Torigian DA;Nazimuddin F;Chen F;Kulikovskaya IM;Soulen MC;McGarvey M;Nelson AM;Gladney WL;Levine BL;Melenhorst JJ;Plesa G;June CH
通讯作者：
June CH

Engineered chimeric antigen receptor-expressing T cells for the treatment of pancreatic ductal adenocarcinoma.

DOI：
10.4161/onci.28327
发表时间：
2014
期刊：
Oncoimmunology
影响因子：
7.2
作者：
Beatty GL
通讯作者：
Beatty GL

Chimeric antigen receptor-modified T cells for the treatment of solid tumors: Defining the challenges and next steps.

DOI：
10.1016/j.pharmthera.2016.06.010
发表时间：
2016-10
期刊：
PHARMACOLOGY & THERAPEUTICS
影响因子：
13.5
作者：
Beatty, Gregory L.;O'Hara, Mark
通讯作者：
O'Hara, Mark

Harnessing the antitumor potential of macrophages for cancer immunotherapy.

DOI：
10.4161/onci.26860
发表时间：
2013-12-01
期刊：
Oncoimmunology
影响因子：
7.2
作者：
Long KB;Beatty GL
通讯作者：
Beatty GL

First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies.

DOI：
10.1158/1078-0432.ccr-16-2272
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Beatty GL;O'Dwyer PJ;Clark J;Shi JG;Bowman KJ;Scherle PA;Newton RC;Schaub R;Maleski J;Leopold L;Gajewski TF
通讯作者：
Gajewski TF