Intratumoral Administration of CCL21-gene Modified Dendritic Cell With Intravenous Pembrolizumab for Advanced NSCLC

CCL21 基因修饰树突状细胞联合静脉注射 Pembrolizumab 治疗晚期 NSCLC

基本信息

批准号：
10626792
负责人：
Aaron Elliott Lisberg
金额：
$ 25.71万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626792
关键词：
Adenovirus Vector Adverse event Antigen-Presenting Cells Antigens Antitumor Response Autologous Autologous Dendritic Cells Biopsy Blood Blood specimen CD8-Positive T-Lymphocytes California Cancer Etiology Cancer Patient Cells Cessation of life Clinical Clinical Data Clinical Research Clinical Trials Clinical Trials Design Complement Correlation Studies Cytometry Data Dendritic Cells Development Development Plans Disease Doctor of Medicine Doctor of Philosophy Dose Drug Targeting Environment Exhibits FOXP3 gene Fostering Funding Gene Modified Goals Granzyme Hematology Human Immune Immune checkpoint inhibitor Immune response Immunofluorescence Immunologic Immunologic Markers Immunologic Monitoring Immunologics Immunophenotyping Immunotherapeutic agent In Situ Injections Institution Interferon Type II Intravenous Lead Ligands Los Angeles Lymphocyte Lymphocyte Activation Lymphocytic Infiltrate Malignant Neoplasms Malignant neoplasm of lung Master of Science Maximum Tolerated Dose Measures Mediating Medicine Mentors Mentorship Myeloid-derived suppressor cells Non-Small-Cell Lung Carcinoma Oncology Outcome PD-1/PD-L1 Pathway interactions Patient-Focused Outcomes Patients Peer Review Phase I Clinical Trials Phenotype Physicians Population Procedures Publishing Regulatory T-Lymphocyte Research Research Methodology Role Safety Sampling Scientist Site Somatic Mutation Specimen T cell receptor repertoire sequencing T-Lymphocyte Therapeutic Tissues Training Translational Research Tumor Tissue Tumor-Infiltrating Lymphocytes United States Universities anti-PD-L1 cancer immunotherapy career development cellular transduction chemokine dendritic cell vaccination enzyme linked immunospot assay exome sequencing experience first-in-human immune checkpoint immune checkpoint blockade improved in situ vaccination inhibitor lymph nodes monocyte mortality nano-string novel novel therapeutic intervention objective response rate pembrolizumab perforin peripheral blood phase I trial predicting response prevent professor programmed cell death ligand 1 programmed cell death protein 1 programs recruit research clinical testing response skills therapy development tumor tumor microenvironment

项目摘要

Project Summary Proposed is a five-year research career development plan focused on evaluating the role of intratumoral (IT) administration of chemokine (C-C motif) ligand 21 (CCL21)-gene modified human monocyte-derived dendritic cells (DC) plus pembrolizumab for the treatment of advanced non-small cell lung cancer (NSCLC). The candidate is an Assistant Professor of Medicine in the Division of Hematology/Oncology at The University of California, Los Angeles (UCLA). The proposal builds on the candidate’s previous translational research and clinical experience in lung cancer immunotherapy by incorporating (1) formal training in clinical/translational research via The Master of Science in Clinical Research Program, (2) conduct of a phase I clinical trial, and (3) evaluation of clinical and correlative data generated on trial. Under the tutelage of his Primary Mentor, Steven Dubinett, M.D., a successful mentor of more than 45 trainees, and strong Mentorship Committee of David Elashoff, Ph.D. and Edward Garon, M.D, M.S., the candidate will gain the skills necessary to become an independent physician scientist. Importantly, he also has strong institutional support to foster his development. Lung cancer is the most common cause of cancer-related mortality in the United States. Programmed cell death-(ligand)1 [PD-(L)1] agents, such as pembrolizumab, have revolutionized treatment of the disease, but a significant proportion of patients still do not benefit. The most commonly proposed reason for the lack of anti- PD-(L)1 efficacy is the absence of tumor infiltrating lymphocytes. One potential approach to overcome this limitation is to utilize in situ vaccination with IT injection of functional antigen presenting cells, such as CCL21 modified DCs, since this chemokine promotes (1) co-localization of lymphocytes and DCs and (2) facilitates T lymphocyte activation. A phase I trial evaluating IT administration of autologous CCL21-DC in advanced NSCLC patients revealed that the procedure is safe, feasible, and promotes effector T lymphocyte infiltration, in addition to systemic immune responses. However, increased PD-L1 expression was observed in the tumor microenvironment following IT injection, suggesting the PD-1 immune checkpoint may be forestalling a more robust CCL21-mediated antitumor response. As a result, it is hypothesized that combined IT CCL21-DC plus pembrolizumab will improve clinical outcomes in patients with advanced NSCLC. The aims of this proposal are to (1) complete a phase I trial of IT CCL21-DC plus pembrolizumab in patients with advanced NSCLC and evaluate (2) blood and (3) tumor tissue collected on trial via mass cytometry (CyTOF) and multiplex immunofluorescence (MIF), which will be guided by the results of four additional correlative analyses planned on trial, to further elucidate remodeling of immunologic pathways as a result of this novel therapeutic approach.

项目摘要提议的是一项五年研究职业发展计划，重点是评估肿瘤内的作用（IT）给药趋化因子（C-C基序）配体21（CCL21） - 基因修饰的人类单核细胞衍生的树突状细胞（DC）和pembrolizumab用于治疗晚期非小细胞肺癌（NSCLC）的治疗。候选人是大学血液学/肿瘤学系医学助理教授加利福尼亚，洛杉矶（加州大学洛杉矶分校）。该提案建立在候选人以前的翻译研究和通过编码（1）临床/翻译中的正式培训在肺癌免疫疗法方面的临床经验通过临床研究计划的科学硕士研究，（2）进行I期临床试验和（3）评估试验中生成的临床和相关数据。在他的主要导师史蒂文的指导下杜比尼特（Dubinett） Elashoff博士以及M.D.的Edward Garon，候选人将获得成为一个必要的技能独立的物理科学家。重要的是，他还拥有强大的机构支持来促进自己的发展。在美国，肺癌是癌症相关死亡率的最常见原因。编程单元格死亡 - （配体）1 [pd-（l）1]，例如pembrolizumab，已经彻底改变了对疾病的治疗大部分患者仍然没有受益。缺乏反 - 的最常见原因 PD-（L）1效率是缺乏肿瘤浸润淋巴细胞。克服这一点的一种潜在方法限制是通过注射功能性抗原呈递细胞（例如CCL21）来利用原位疫苗接种修饰的DC，因为该趋化因子促进了（1）淋巴细胞和DC的共定位，并且（2）促进T 淋巴细胞激活。一项评估IT施用自体CCL21-DC的I期试验 NSCLC患者显示，该过程是安全，可行的，并促进淋巴细胞浸润，除了系统性免疫反应。但是，在肿瘤中观察到PD-L1表达增加注射后的微环境，这表明PD-1免疫检查站可能正在阻止更多强大的CCL21介导的抗肿瘤反应。结果，假设将其组合在一起CCL21-DC Plus Pembrolizumab将改善晚期NSCLC患者的临床结果。该提议的目的是（1）在患有晚期NSCLC和评估（2）血液和（3）在试验中通过质量细胞仪（Cytof）和多重的肿瘤组织免疫荧光（MIF）将由计划的其他四个相关分析的结果指导在试验中，由于这种新型的治疗方法，以进一步阐明免疫途径的重塑。