Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients

项目1：评估LAG3和PD-1在黑色素瘤患者中的协同作用

• 批准号: 10683756
• 负责人: Dario AA Vignali
• 金额: $ 36.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683756
• 关键词: Aftercare; Biological Markers; Biopsy; Blinded; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cancer Patient; Cell physiology; Cell surface; Cells; Cessation of life; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cytometry; Enrollment; Exhibits; Functional disorder; Genetic Transcription; Goals; Homeostasis; IL6 gene; Immune; Immune System Diseases; Immune response; Immunotherapeutic agent; Immunotherapy; Malignant Neoplasms; Mediating; Metalloproteases; Metastatic Melanoma; Modality; Molecular; NRP1 gene; Nivolumab; PD-1 blockade; PD-1/PD-L1; PTPRC gene; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Phase; Phase II Clinical Trials; Phenotype; Plasma; Prognosis; Proliferating; Regimen; Regulation; Resistance; Series; Signal Transduction; Skin Cancer; T cell receptor repertoire sequencing; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic Clinical Trial; Tissues; Tumor Immunity; Tumor-Infiltrating Lymphocytes; anti-PD-1; anti-PD1 therapy; arm; biomarker identification; cancer imaging; cancer infiltrating T cells; cohort; effector T cell; immune resistance; improved; innovation; insight; interest; liquid crystal polymer; melanoma; mouse model; nano-string; novel; patient population; patient response; peripheral blood; predict responsiveness; programmed cell death protein 1; programs; randomized, clinical trials; receptor; receptor expression; resistance mechanism; response; response biomarker; single-cell RNA sequencing; spectrograph; standard of care; synergism; targeted treatment; therapeutic target; tocilizumab; trial design; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT: PROJECT 1 Melanoma is the most aggressive skin cancer and causes over 10,000 deaths per year in the US. While great strides have been made in the treatment of melanoma, many patients are still non-responsive to immunotherapy. Understanding the function of PD1 and LAG3 on the immune response in both the tumor and periphery of patients is critical to the progress of immunotherapy in melanoma. Although LAG3 is the third ‘checkpoint’ to be targeted with >10 agents in clinical trials, we still know very little about how LAG3 blockade, alone or with anti- PD1, impacts the immune response to melanoma. We have demonstrated synergistic PD1/LAG3 combinatorial immunotherapy in mouse models of cancer and clear evidence of clinical benefit from dual inhibitory receptor (IR) blockade has stimulated anti-PD1 and anti-LAG3 trials in cancer patients failing previous immunotherapies. Our overarching hypothesis is that LAG3 and PD1 single-agent blockades differentially regulate, and synergize to promote, CD8+ T cell function in the tumor and peripheral blood of MPs and that a LAG3-dominant IR module in peripheral CD8+ T cells downregulates patient response to PD1-targeted therapy. Specific Aim 1. What is the mechanism of anti-PD1 (nivo) and anti-LAG3 (rela), alone and in combination, on the phenotype and function of CD8+ T cells? We have initiated accrual in a unique biomarker-focused phase II randomized clinical trial to evaluate the combination of anti-PD1 and/or anti-LAG3 therapy in treatment naïve melanoma patients. We hypothesize that T cell activation and proliferation pathways are differentially regulated in CD8+ T cells by anti-PD1 vs. anti-PD1/LAG3 and that unique synergistic molecular programs will be revealed by this immunotherapeutic combination in treatment-naïve patients with metastatic melanoma. Our novel trial design will assess the mechanistic impact of anti-PD1 and/or LAG3 immunotherapy in peripheral and tumor CD8+ T cells. Specific Aim 2. Does IL6 drive a LAG3-dominant IR module in peripheral CD8+ T cells, and does it predict responsiveness to immunotherapy? We have recently made a series of novel findings regarding IR expression in peripheral CD8+ T cells that implies a novel mechanism of immune resistance in melanoma patients. We hypothesize that IL6-driven systemic immune dysfunction and subsequent resistance to anti-PD1 therapy is driven by a LAG3-dominant IR module and that this dysfunction can be ameliorated by anti-LAG3/PD1 blockade. This project will [i] define new biomarkers of response and/or resistance to nivo, rela, and the combination; [ii] potentially identify a patient population that will optimally benefit from LAG3-based therapies; and [iii] develop novel combinatorial immunotherapies of increased efficacy in melanoma.

项目摘要/摘要：项目 1 黑色素瘤是最具侵袭性的皮肤癌，在美国每年导致超过 10,000 人死亡。虽然很棒 黑色素瘤的治疗已经取得了长足的进步，但许多患者仍然对免疫疗法没有反应。 了解 PD1 和 LAG3 对肿瘤和外周免疫反应的功能 患者对于黑色素瘤免疫治疗的进展至关重要。虽然 LAG3 是第三个“检查点” 在临床试验中针对超过 10 种药物，我们仍然对单独或与抗-LAG3 阻断剂如何阻断知之甚少。 PD1 影响对黑色素瘤的免疫反应。我们已经证明了 PD1/LAG3 的协同组合 小鼠癌症模型中的免疫疗法以及双抑制受体临床获益的明确证据 (IR) 封锁刺激了针对先前免疫疗法失败的癌症患者的抗 PD1 和抗 LAG3 试验。 我们的首要假设是 LAG3 和 PD1 单药阻断有差异性调节和协同作用 促进肿瘤和 MP 外周血中的 CD8+ T 细胞功能，以及 LAG3 主导的 IR 模块 外周 CD8+ T 细胞下调患者对 PD1 靶向治疗的反应。 具体目标 1. 单独和联合使用抗 PD1 (nivo) 和抗 LAG3 (rela) 的机制是什么？ CD8+ T 细胞的表型和功能？我们已经启动了以独特的生物标志物为重点的应计项目 II 期随机临床试验，评估抗 PD1 和/或抗 LAG3 联合疗法的治疗效果 幼稚黑色素瘤患者。我们假设 T 细胞激活和增殖途径存在差异 CD8+ T 细胞中抗 PD1 与抗 PD1/LAG3 的调节，独特的协同分子程序将 这种免疫治疗组合在未经治疗的转移性黑色素瘤患者中揭示了这一点。我们的 新颖的试验设计将评估抗 PD1 和/或 LAG3 免疫疗法对外周和 肿瘤 CD8+ T 细胞。 具体目标 2. IL6 是否驱动外周 CD8+ T 细胞中 LAG3 主导的 IR 模块，并且它是否预测 对免疫治疗的反应？我们最近取得了一系列关于 IR 的新发现 外周 CD8+ T 细胞中的表达暗示黑色素瘤中免疫抵抗的新机制 患者。我们假设 IL6 驱动的全身免疫功能障碍以及随后的抗 PD1 耐药性 治疗是由 LAG3 主导的 IR 模块驱动的，并且这种功能障碍可以通过抗 LAG3/PD1 来改善 封锁。 该项目将[i]定义对 nivo、rela 及其组合的反应和/或耐药性的新生物标志物； [ii] 潜在地识别出最能从基于 LAG3 的疗法中获益的患者群体；和[三] 开发新的组合免疫疗法，以提高黑色素瘤的疗效。