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

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，但许多患者对免疫治疗仍然没有反应。 了解PD1和LAG3在肿瘤及周围免疫反应中的作用 患者对黑色素瘤免疫治疗的进展至关重要。尽管LAG3是第三个将成为 在临床试验中以10种药物为靶点，我们仍然对LAG3如何单独或与抗病毒药物一起阻断知之甚少 PD1，影响对黑色素瘤的免疫反应。我们已经证明了PD1/LAG3组合的协同作用 双抑制受体在小鼠肿瘤模型中的免疫治疗及其临床益处的明确证据 (IR)封锁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单药阻断具有不同的调节和协同作用 为了促进MPS肿瘤和外周血中CD8+T细胞的功能，以及LAG3主导的IR模块 在外周，CD8+T细胞下调患者对PD1靶向治疗的反应。 具体目的1.抗PD1(Nivo)和抗LAG3(RelA)单独和联合作用的机制是什么？ CD8+T细胞的表型和功能？我们已经在一种独特的生物标记物中启动了应计 评价联合应用抗PD1和/或抗LAG3治疗的II期随机临床试验 天真的黑色素瘤患者。我们假设T细胞激活和增殖途径是不同的 在CD8+T细胞中受抗PD1和抗PD1/LAG3调节，独特的协同分子程序将是 这种免疫治疗组合在治疗转移性黑色素瘤的幼稚患者中显示。我们的 新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。 特定目的2.IL6是否在外周CD8+T细胞中驱动LAG3主导的IR模块，并且它是否预测 对免疫疗法的反应？我们最近对IR有了一系列新的发现 外周血CD8+T细胞表达提示黑色素瘤免疫抵抗的新机制 病人。我们假设IL6导致的系统性免疫功能障碍和随后的对抗PD1的抵抗 治疗是由LAG3主导的IR模块驱动的，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/或抗性的新生物标记物； [ii]潜在地确定将从基于LAG3的疗法中获得最佳益处的患者群体；以及[iii] 开发提高黑色素瘤疗效的新型组合免疫疗法。

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.