Understanding Immunotype, a Novel Biomarker for Checkpoint Blockade Resistance

摘要 据估计，美国44%的癌症患者有资格接受免疫检查站封锁 (ICB)。FDA批准的ICB药物包括α-PD-1和α-CTLA-4抗体，但大多数患者不这样做 受益，因为他们的肿瘤对这些药物具有抗药性。ICB治疗费用昂贵，可能导致严重的 毒性。对ICB耐药癌症患者进行前瞻性识别将降低不必要的风险和成本 并让患者有机会寻求更合适的治疗选择。为了解决未得到满足的对 ICB有效性的外周血液生物标志物，我们对ICB治疗的患者进行了免疫图谱分析 黑色素瘤，使用多参数流式细胞术来表征治疗前外周血中的免疫细胞。 我们的分析揭示了一种新的外周血液免疫图谱--我们称之为免疫类型-1(IT-1)，定义为 部分是由于LAG-3+CD8+T细胞的存在--作为ICB耐药性的一个有前途的生物标志物。这一发现是 在转移性尿路上皮癌的独立数据集中得到验证。IT-1患者总体表现较差 存活率、无进展存活率和对α-PD-1阻断的反应率。利用我们在世界上的领导地位 ICBS的临床发展，我们已经组装了最大的外周血样生物库之一 &gt；600名接受ICB治疗的癌症患者。在这项提议中，我们的目标是检验IT-1是一个PAN-1的假设。 ICB的癌症生物标志物，反映了疲惫的、肿瘤特异性的LAG-3+CD8+T细胞群体，其功能 使用α-LAG-3阻滞剂可恢复治疗效果。具体目标是：1)表型 并从功能上表征外周血LAG-3+CD8+T细胞群并确定该人群 在具有IT-1表型的患者的肿瘤微环境中被表达；2)确定这种联系 在不同癌症类型的ICB治疗患者中IT-1与临床结果之间的关系；3)评估IT-1是否 确定对relatlimab(α-LAG-3)+nivolumab(α-PD-1)有反应的患者。我们的项目植根于强大的 临床数据，从而可能确定一个基于机制的、临床上可实施的、大多数 重要的是，在治疗上是可行的。

ABSTRACT An estimated 44% of patients with cancer in the United States are eligible to receive immune checkpoint blockade (ICB). FDA-approved ICB agents include α-PD-1 and α-CTLA-4 antibodies, but the majority of patients do not benefit because their tumors are resistant to these agents. ICB treatment is expensive and may lead to serious toxicity. Prospective identification of patients with ICB-resistant cancers would reduce unnecessary risk and cost and give patients opportunities to seek more appropriate treatment options. To address the unmet need for a peripheral blood biomarker for ICB effectiveness, we performed immune profiling of ICB-treated patients with melanoma, using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. Our analyses revealed a new peripheral blood immune profile—which we called Immunotype-1 (IT-1), defined in part by the presence LAG-3+CD8+ T cells—as a promising biomarker of ICB resistance. This finding was validated in an independent dataset of metastatic urothelial cancer. Patients with IT-1 have inferior overall survival, progression-free survival, and response rates to α-PD-1 blockade. Leveraging our leadership in the clinical development of ICBs, we have assembled one of the largest biobanks of peripheral blood samples from >600 ICB-treated patients across cancer types. In this proposal, we aim to test the hypothesis that IT-1 is a pan- cancer biomarker for ICB, reflecting an exhausted, tumor-specific LAG-3+CD8+ T cell population whose function can be recovered for therapeutic benefit using α-LAG-3 blockade. The Specific Aims are to: 1) Phenotypically and functionally characterize the peripheral blood LAG-3+CD8+ T cell population and determine if this population is represented in the tumor microenvironment in patients with the IT-1 phenotype; 2) Determine the association between IT-1 and clinical outcome in ICB-treated patients across cancer types; and 3) Assess whether IT-1 identifies patients who will respond to relatlimab (α-LAG-3) + nivolumab (α-PD-1). Our project is rooted in strong clinical data and thus likely to identify a biomarker that is mechanism-based, clinically implementable, and most importantly, therapeutically actionable.