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

项目摘要 提出的是一个为期五年的研究职业发展计划，重点是评估肿瘤内（IT） 趋化因子（C-C基序）配体21（CCL 21）基因修饰的人单核细胞衍生的树突状细胞的施用 细胞（DC）加派姆单抗用于治疗晚期非小细胞肺癌（NSCLC）。的 候选人是一名助理教授，在血液学/肿瘤学系的大学 加州、洛杉矶（UCLA）。该提案建立在候选人以前的翻译研究基础上， 肺癌免疫治疗的临床经验，包括（1）临床/翻译的正式培训 通过临床研究计划理学硕士进行研究，（2）进行I期临床试验，以及（3） 评价试验产生的临床和相关数据。在他的初级导师史蒂文的指导下， Dubinett，医学博士，超过45名学员的成功导师，以及强大的大卫导师委员会 Elashoff博士和爱德华·加伦医学博士候选人将获得成为一名 独立医生科学家。重要的是，他还有强大的机构支持来促进他的发展。 肺癌是美国癌症相关死亡的最常见原因。程序性细胞 死亡-（配体）1 [PD-（L）1]药物，如派姆单抗，已经彻底改变了疾病的治疗，但 很大一部分患者仍然没有受益。最常见的原因是缺乏抗- PD-（L）1功效是不存在肿瘤浸润淋巴细胞。一种可能的解决方法是 限制是利用IT注射功能性抗原呈递细胞（如CCL 21）的原位接种 修饰的DC，因为这种趋化因子促进（1）淋巴细胞和DC的共定位，并且（2）促进T 淋巴细胞活化一项评估晚期肺癌患者IT给予自体CCL 21-DC的I期试验 非小细胞肺癌患者显示，该手术是安全可行的，并促进效应T淋巴细胞浸润， 以及全身免疫反应。然而，在肿瘤中观察到PD-L1表达增加， IT注射后的微环境，表明PD-1免疫检查点可能会阻止更多的免疫反应。 CCL 21介导的抗肿瘤反应。因此，假设组合的IT CCL 21-DC加 pembrolizumab将改善晚期NSCLC患者的临床结局。这项建议的目的是 （1）在晚期NSCLC患者中完成IT CCL 21-DC+派姆单抗的I期试验， 通过质谱细胞术（CyTOF）和多重分析评价试验中采集的（2）血液和（3）肿瘤组织 免疫荧光（MIF），这将由计划的四项额外相关分析的结果指导 在试验中，进一步阐明作为这种新的治疗方法的结果的免疫途径的重塑。

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.