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: 10270231
• 负责人: Dario AA Vignali
• 金额: $ 36.39万
• 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/10270231
• 关键词: Aftercare; Biological Markers; Biopsy; Blinded; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Etiology; Cancer Model; Cancer Patient; Cell physiology; Cell surface; Cells; Cessation of life; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cutaneous Melanoma; Cytometry; Enrollment; Exhibits; Functional disorder; Genetic Transcription; Goals; IL6 gene; Immune; Immune System Diseases; Immune response; Immunotherapeutic agent; Immunotherapy; Malignant Neoplasms; Mediating; Metalloproteases; Metastatic Melanoma; Modality; Molecular; Mus; 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; Randomized Clinical Trials; 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; base; cancer imaging; 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; receptor; receptor expression; resistance mechanism; response; response biomarker; single-cell RNA sequencing; 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 黑色素瘤是最具侵略性的皮肤癌，在美国每年导致10,000多人死亡。虽然很棒 在治疗黑色素瘤方面已经取得了进步，许多患者仍然对免疫疗法无反应。 了解pd1和lag3在肿瘤和周围的免疫激素上的功能 患者对黑色素瘤免疫疗法的进展至关重要。虽然lag3是第三个“检查点” 在临床试验中，针对> 10个代理，我们仍然对lag3封锁单独或抗抗 PD1会影响黑色素瘤的免疫增强响应。我们已经证明了协同的PD1/LAG3组合 癌症小鼠模型中的免疫疗法和双重抑制受体的临床益处的明确证据 （ir）桶已经刺激了先前免疫疗法失败的癌症患者的抗PD1和抗LAG3试验。 我们的总体假设是lag3和pd1单位封锁对调节的调节不同，并协同作用 促进MPS的肿瘤和外周血中的CD8+ T细胞功能和滞后IR模块 在外围CD8+ T细胞中，患者对PD1靶向治疗的反应下调。 特定目标1。抗PD1（NIVO）和抗LAG3（RELA）的机制是什么，单独和组合 在CD8+ T细胞的表型和功能上？我们已经以独特的生物标志物为中心发起了积分 II期随机临床试验，以评估抗PD1和/或抗LAG3治疗的组合 我们假设T细胞激活和增殖途径是差异的 通过抗PD1与抗PD1/lag3在CD8+ T细胞中调节，独特的协同分子程序将是 这种免疫治疗组合在没有转移性黑色素瘤的患者中揭示了。我们的 新型试验设计将评估抗PD1和/或LAG3免疫疗法对外周和/或 肿瘤CD8+ T细胞。 特定的目标2。是否在外围CD8+ T细胞中驱动lag3占主导地位的IR模块，并且可以预测 对免疫疗法的反应？我们最近做了一系列有关IR的新颖发现 在外周三+ T细胞中的表达暗示了黑色素瘤免疫抗性的新机制 患者。我们假设IL6驱动的全身免疫功能障碍以及随后对抗PD1的阻力 治疗是由LAG3占主导地位的IR模块驱动的，并且可以通过抗LAG3/PD1改善这种功能障碍 glocade。 该项目将[I]定义对Nivo，Rela和组合的反应和/或抵抗的新生物标志物； [ii]有可能确定将从基于LAG3的疗法中最佳受益的患者人群；和[iii] 开发出了黑色素瘤效率提高的新型组合免疫疗法。