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.

项目总结/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。而大 尽管在黑色素瘤的治疗方面已经取得了长足的进步，但许多患者仍然对免疫疗法无反应。 了解PD 1和LAG 3在肿瘤和外周免疫应答中的功能， 患者是黑色素瘤免疫治疗进展的关键。虽然LAG 3是第三个“检查点”， 尽管在临床试验中使用了>10种药物靶向，但我们仍然对LAG 3单独或与抗LAG 3一起阻断LAG 3的作用知之甚少。 PD 1影响对黑色素瘤的免疫反应。我们已经证明了协同PD 1/LAG 3组合 小鼠癌症模型中免疫治疗和双重抑制受体的临床益处的明确证据 (IR)阻断刺激了在先前免疫疗法失败的癌症患者中进行抗PD 1和抗LAG 3试验。 我们的总体假设是LAG 3和PD 1单药阻断差异调节，并协同作用 促进，CD 8 + T细胞功能在肿瘤和外周血的MP和LAG 3-显性IR模块 外周血CD 8 + T细胞下调患者对PD 1靶向治疗的反应。 具体目标1。抗PD 1（nivo）和抗LAG 3（rela）单独使用和联合使用的机制是什么， 对CD 8 + T细胞的表型和功能的影响？我们已经启动了一个独特的以生物标记为重点的 评价抗PD 1和/或抗LAG 3联合治疗的II期随机临床试验 初治黑素瘤患者。我们假设T细胞活化和增殖途径是不同的， 抗PD 1与抗PD 1/LAG 3在CD 8 + T细胞中的调节，并且独特的协同分子程序将被 在转移性黑色素瘤初治患者中，我们 新的试验设计将评估抗PD 1和/或LAG 3免疫疗法在外周和外周血中的机制影响， 肿瘤CD 8 + T细胞。 具体目标2。IL 6是否驱动外周CD 8 + T细胞中LAG 3主导的IR模块，以及它是否预测 对免疫疗法的反应我们最近在IR方面取得了一系列新的发现， 在外周CD 8 + T细胞中的表达，这意味着黑色素瘤中免疫抵抗的新机制 患者我们假设IL 6驱动的全身免疫功能障碍和随后的抗PD 1抗体耐药性可能与IL-10的表达有关。 治疗是由LAG 3主导的IR模块驱动的，并且这种功能障碍可以通过抗LAG 3/PD 1 封锁 该项目将[i]定义对nivo、rela和组合的响应和/或抗性的新生物标志物; [ii]潜在地识别将最佳地受益于基于LAG 3的疗法的患者群体;以及[iii] 开发在黑素瘤中提高功效的新型组合免疫疗法。