Neoadjuvant immunotherapy approaches to early stage melanoma

早期黑色素瘤的新辅助免疫治疗方法

• 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
• 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

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.

项目摘要 - 项目3 不需要改善高风险II期黑色素瘤患者的存活率。目前， II期黑色素瘤的治疗是监测迫切无法接受的高复发率和死亡率 单独观察到手术。前哨淋巴结（SLN）是由原发性肿瘤排出的第一个淋巴结 并且不仅是转移癌细胞的靶标，而且是肿瘤抗原的免疫传感器 由原发性皮肤黑色素瘤释放。我们在排水淋巴结（LN）转移模型中的初步数据 在黑色素瘤转移到LN之前和期间，髓样细胞群体的显着增加。我们 提议LN中的这些变化可能会损害其行动能力（i）作为守门人，以防止黑色素瘤 通过淋巴机扩散，（ii）作为能够控制局部的抗原特异性T细胞免疫的讲师 疾病并干预血源扩散。那就是我们的总体假设是 防止局部和遥远黑色素瘤蔓延的SLN取决于其免疫健康， 这是由淋巴结 - 居住髓样的免疫刺激能力确定的 细胞。在AIM 1中，博士。 karakousis（临床共同项目负责人（PL））和Schuchter（共同研究器（I））将进行 新辅助pembrolizumab在IIB/C临床IIB/C黑色素瘤中的研究者引发的II期临床试验。 使用该临床试验和阶段匹配的历史同志的原发性肿瘤和前哨LNS（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。我们将使用由Wherry博士（CO-I）和 假设驱动的方法以我们的发现为巨噬细胞在准备转移性中的作用的指导 利基（Beatty，Applied Co-PL）来确定SLN阳性和阴性患者与治疗相关的变化。 然后，合成模型的研究将告知髓样细胞子集在指导LN生物学变化中的作用 由黑色素瘤发育及其对抗PD1治疗的影响引发。 AIM 2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对抗PD1的反应的可能性 治疗。在Co-Pls Drs的领导下。赫林和比蒂，我们将使用多个组织和基于细胞 分析从我们的II期试验和阶段匹配的历史控制中收集的样本的测定法 定义与髓样细胞（包括树突状细胞）的T细胞相互作用及其对治疗反应的影响 和临床结果。此外，我们将确定临床上可用的TLR激动剂是否可以增强 排水LN的免疫刺激能力，并在此过程中提高抗PD-1治疗的效率 人源化小鼠对患者衍生的Xenographtics提出了挑战，这些Xenographictics具有高忠诚的早期黑色素瘤。 影响：我们预计新辅助免疫疗法将大大降低SLN的正率警告未来 旨在改变临床实践的随机研究。我们希望将SLN确定为重要 黑色素瘤发病机理和免疫疗法的临床结局的决定因素。