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

项目摘要 提出了一项为期五年的研究职业发展计划，重点评估肿瘤内(IT)的作用 趋化因子(C-C基序)配体21(CCL21)基因修饰的人单核细胞来源树突状细胞的应用 细胞(DC)加培溴利珠单抗治疗晚期非小细胞肺癌(NSCLC)。这个 候选人是加州大学血液学/肿瘤学系医学助理教授 加州大学洛杉矶分校(UCLA)。该提案建立在候选人之前的翻译研究和 肺癌免疫治疗的临床经验：(1)正规的临床/翻译培训 通过临床研究硕士项目进行的研究，(2)进行I期临床试验，以及(3) 对试验中产生的临床和相关数据进行评估。在他的主要导师史蒂文的指导下 杜比内特，医学博士，超过45名学员的成功导师，大卫的强大导师委员会 Elashoff博士和Edward Garon，M.D.，M.S.，候选人将获得成为一名 独立的内科科学家。重要的是，他也有强有力的制度支持来促进他的发展。 肺癌是美国最常见的癌症相关死亡原因。程控单元 死亡(配体)1[PD-(L)1]药物，如培溴利珠单抗，使这种疾病的治疗发生了革命性的变化，但 相当大比例的患者仍然没有受益。最常被提出的原因是缺乏反- PD-(L)1疗效是无肿瘤浸润性淋巴细胞。克服这一问题的一个潜在方法是 限制是利用IT注射功能性抗原提呈细胞的原位接种，如CCL21 修饰的DC，因为这种趋化因子促进(1)淋巴细胞和DC的共定位和(2)促进T细胞 淋巴细胞活化。晚期自体CCL21-DC IT管理的I期试验评价 NSCLC患者显示，该方法安全、可行，并促进了效应性T淋巴细胞的浸润， 除了全身免疫反应。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免疫检查点可能正在预防更多 CCL21介导的强大的抗肿瘤反应。因此，假设将IT CCL21-DC PLUS 培溴利珠单抗将改善晚期非小细胞肺癌患者的临床结果。这项提议的目的是 为(1)完成IT CCL21-DC联合培溴利珠单抗治疗晚期非小细胞肺癌患者的I期试验 通过质量细胞术(CyTOF)和多重分析评估(2)血液和(3)在试验中收集的肿瘤组织 免疫荧光(MIF)，将以计划中的另外四个相关分析的结果为指导 在试验中，进一步阐明由于这种新的治疗方法而导致的免疫途径的重构。

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.