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点封锁 （ICB）。FDA批准的ICB药物包括α-PD-1和α-CTLA-4抗体，但大多数患者没有 因为他们的肿瘤对这些药物有抵抗力。ICB治疗费用昂贵，可能导致严重的 毒性对ICB耐药癌症患者的前瞻性识别将减少不必要的风险和成本 让患者有机会寻求更合适的治疗方案。为了满足未得到满足的需求， 外周血生物标志物的ICB有效性，我们进行了免疫分析的ICB治疗的患者， 黑色素瘤，使用多参数流式细胞术表征预处理外周血中的免疫细胞。 我们的分析揭示了一种新的外周血免疫谱，我们称之为免疫型-1（IT-1）， 部分是由于LAG-3+ CD 8 + T细胞的存在-作为ICB抗性的有希望的生物标志物。该结果 在转移性尿路上皮癌的独立数据集中得到验证。IT-1患者的总体 生存期、无进展生存期和对α-PD-1阻断的应答率。利用我们在 ICBs的临床开发，我们已经组装了最大的外周血样本生物库之一， >600名ICB治疗的癌症患者。在这个建议中，我们的目标是测试的假设，IT-1是一个泛- ICB的癌症生物标志物，反映了耗尽的肿瘤特异性LAG-3+ CD 8 + T细胞群，其功能 可以使用α-LAG-3阻断剂恢复治疗益处。具体目标是：1）表型 并功能性表征外周血LAG-3+ CD 8 + T细胞群，并确定该群是否 在具有IT-1表型的患者的肿瘤微环境中表现; 2）确定与肿瘤微环境中的T细胞亚群的相关性。 在ICB治疗的不同癌症类型的患者中，IT-1与临床结果之间的关系;以及3）评估IT-1是否 确定将对relatlimab（α-LAG-3）+ nivolumab（α-PD-1）产生应答的患者。我们的项目植根于强大的 临床数据，因此可能鉴定基于机制的、临床上可实施的和大多数生物标志物。 更重要的是，治疗上可行。

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.