Neoadjuvant immunotherapy approaches to early stage melanoma

早期黑色素瘤的新辅助免疫治疗方法

基本信息

批准号：
10268746
负责人：
Meenhard F Herlyn
金额：
$ 46.67万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-03 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10268746
关键词：
Agonist Biological Biological Assay Biology Blocking Antibodies Blood Cell Communication Cells Cellular biology Clinical Clinical Research Clinical Trials Cutaneous Melanoma Data Defect Dendritic Cells Development Disease Distant Future Gatekeeping Genetic Transcription Goals Health Hematogenous Hematogenous Spread Human Immune Immunity Immunologic Surveillance Immunologics Immunophenotyping Immunotherapy Investigation Leadership Lymphatic Lymphatic Metastasis Lymphatic Spread Lymphatic System Malignant Neoplasms Metastatic Neoplasm to Lymph Nodes Modeling Mus Myelogenous Myeloid Cells Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Organ Outcome PD-1 blockade Pathogenesis Pathologic Patients Phase II Clinical Trials Pliability Population Positive Lymph Node Primary Neoplasm Productivity Randomized Recurrence Research Design Research Personnel Role Sampling Sentinel Lymph Node Skin Skin Cancer Surveys T-Lymphocyte Testing Tissues Tumor Antigens Tumor Burden Tumor Tissue Work anti-PD-1 anti-PD1 antibodies anti-PD1 therapy anti-tumor immune response antigen-specific T cells base cancer cell clinical effect clinical practice clinical risk clinically significant cohort design draining lymph node exhaust exhaustion high risk humanized mouse immune health immune resistance improved improved outcome instructor lymph nodes macrophage melanoma mortality mouse model novel patient derived xenograft model pembrolizumab peripheral blood phase II trial pre-clinical prevent resistance mechanism response sensor survival outcome therapy resistant treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

Project Summary – Project 3 There is an unmet need to improve the survival of patients with high-risk Stage II melanoma. Currently, the treatment for Stage II melanoma is surveillance despite unacceptably high recurrence and mortality rates observed with surgery alone. The sentinel lymph node (SLN) is the first lymph node drained by a primary tumor and is not only a target for metastasizing cancer cells but also an immunological sensor of tumor antigens released by primary cutaneous melanoma. Our preliminary data in a draining lymph node (LN) metastasis model shows striking increases in myeloid cell populations prior to and during melanoma metastasis to the LN. We propose that these changes in the LN may compromise its ability to act (i) as a gatekeeper to prevent melanoma spread via the lymphatics and (ii) as an instructor of antigen-specific T cell immunity capable of controlling local disease and intervening on hematogenous spread. Thus, our overall hypothesis is that the capacity of the SLN to protect against locoregional and distant melanoma spread is dependent on its immune health, which is pliable and determined by the immunostimulatory capacity of lymph node-resident myeloid cells. In Aim 1, Drs. Karakousis (Clinical co-Project Leader (PL)) and Schuchter (co-Investigator (I)) will conduct an investigator-initiated Phase II clinical trial of neoadjuvant pembrolizumab in clinical Stage IIB/C melanoma. Using primary tumors and sentinel LNs (SLN) from both this clinical trial and stage-matched historical cohorts, we will determine the effects of immunotherapy on the immunophenotype and anti-metastatic capacity of the SLN. We will use a combination of unbiased global profiling strategies pioneered by Dr. Wherry (co-I) and hypothesis-driven approaches guided by our discoveries into the role of macrophages in preparing the metastatic niche (Beatty, Applied co-PL) to determine therapy-associated changes in SLN-positive and -negative patients. Studies in syngeneic models will then inform the role of myeloid cell subsets in directing changes in LN biology triggered by melanoma development and their impact on anti-PD1 therapy. Aim 2 will test the hypothesis that the immunostimulatory capacity of lymph node dendritic cells determines the likelihood of response to anti-PD1 therapy. Under the leadership of co-PLs Drs. Herlyn and Beatty , we will use multiplex tissue- and cell-based assays to analyze samples collected from our Phase II trial and stage-matched historical controls with the goal to define T cell interactions with myeloid cells, including dendritic cells, and their impact on treatment response and clinical outcomes. In addition, we will determine if clinically-available TLR agonists can enhance the immunostimulatory capacity of the draining LN and in doing so, improve the efficacy of anti-PD-1 therapy using humanized mice challenged with patient-derived xenografts which model early stage melanoma with high fidelity. Impact: We anticipate neoadjuvant immunotherapy will substantially reduce SLN positivity rates warranting future randomized studies designed to change clinical practice. We expect to identify the SLN as an important determinant of melanoma pathogenesis and clinical outcomes to immunotherapy.

项目总结 – 项目 3 目前，提高高危 II 期黑色素瘤患者的生存率的需求尚未得到满足。尽管复发率和死亡率高得令人无法接受，但 II 期黑色素瘤的治疗仍然是监测仅通过手术观察到的前哨淋巴结（SLN）是原发肿瘤引流的第一个淋巴结。不仅是癌细胞转移的靶点，也是肿瘤抗原的免疫传感器我们在引流淋巴结（LN）转移模型中发布的初步数据。显示黑色素瘤转移至淋巴结之前和期间骨髓细胞群显着增加。提出 LN 的这些变化可能会损害其作为预防黑色素瘤的看门人的能力通过淋巴管传播，并且 (ii) 作为抗原特异性 T 细胞免疫的指导者，能够控制局部因此，我们的总体假设是，病毒的能力。 SLN 预防局部和远处黑色素瘤扩散取决于其免疫健康状况，它是柔韧的，由淋巴结驻留的骨髓细胞的免疫刺激能力决定在目标 1 中，Karakousis 博士（临床联合项目负责人 (PL)）和 Schuchter（联合研究员 (I)）将进行一项由研究者发起的新辅助派姆单抗治疗临床 IIB/C 期黑色素瘤的 II 期临床试验。使用来自本临床试验和阶段匹配历史队列的原发肿瘤和前哨淋巴结（SLN），我们将确定免疫疗法对免疫表型和抗转移能力的影响 SLN。我们将结合使用由 Wherry 博士（co-I）和假设驱动的方法以我们对巨噬细胞在准备转移细胞中的作用的发现为指导利基（Beatty，Applied co-PL）以确定 SLN 阳性和阴性患者的治疗相关变化。同基因模型的研究将揭示骨髓细胞亚群在指导淋巴结生物学变化中的作用由黑色素瘤发展引发及其对抗 PD1 治疗的影响将检验以下假设：淋巴结树突状细胞的免疫刺激能力决定了抗 PD1 反应的可能性在共同 PL 博士 Herlyn 和 Beatty 的领导下，我们将使用基于组织和细胞的多重疗法。分析从我们的 II 期试验和阶段匹配的历史对照中收集的样本，以达到目标定义 T 细胞与骨髓细胞（包括树突状细胞）的相互作用及其对治疗反应的影响此外，我们将确定临床上可用的 TLR 激动剂是否可以增强疗效。引流淋巴结的免疫刺激能力，从而提高抗 PD-1 治疗的疗效人源化小鼠接受来自患者的异种移植物的挑战，该异种移植物以高保真度模拟早期黑色素瘤。影响：我们预计新辅助免疫治疗将大幅降低 SLN 阳性率，值得未来我们希望将 SLN 确定为一个重要的随机研究。黑色素瘤发病机制和免疫治疗临床结果的决定因素。