B cells in autoimmunity following checkpoint blockade therapy

项目概要 抗 CTLA4 和抗 PD1 抗体的联合检查点阻断 (CCB) 疗法导致高发病率 肿瘤消退，并已被 FDA 批准用于晚期患者的前期治疗 黑色素瘤，目前正在其他肿瘤中进行评估。不幸的是，CCB 也导致了高利率 免疫相关不良事件 (IRAE)，超过一半的治疗患者经历 3-4 级 IRAE 导致超过三分之一的患者停止治疗。因此，IRAE 的开发仍然是一个主要的 联合检查点阻断在人类癌症中的最佳应用的障碍。从实际出发 从长远来看，如果自身免疫风险增加的患者能够 在临床毒性之前被识别，并且通过先发制人的干预降低自身免疫的风险，而无需 影响临床疗效。该应用程序建立在我们最近的研究基础上，旨在评估治疗引起的变化 与 IRAE 发生风险相关的免疫细胞。在这些研究中，我们观察到 CCB 治疗会导致 B 细胞发生明显的变化模式，这种变化先于频率变化并与频率相关。 以及 IRAE 的时间。相反，治疗诱导的循环 CD4 或 CD8 T 细胞增殖或定量 其他免疫细胞（NK 细胞、单核细胞）的变化与 IRAE 的发生无关，也不能预测 IRAE 的发生。 我们假设，B 细胞早期发生变化的患者识别出一组处于发生以下疾病的高风险人群： CCB 后的自身免疫。迄今为止，临床前模型尚未概括 CCB 相关的谱 在临床中观察到的自身免疫，支持了人体研究的需要。具体目标是： 目标 1. 验证 B 细胞变化作为接受治疗的黑色素瘤患者 IRAE 风险增加的生物标志物 CCB 治疗并评估 CCB 治疗对 B 细胞亚群和功能的长期影响 在自然发生的自身免疫的背景下观察到的那些。 目标 2. 鉴定 CCB 治疗后扩增的 B 细胞的抗原靶标，并检查它们的能力 充当抗原呈递细胞。 目标 3. 检查接受治疗的患者中 T 辅助亚群细胞在激活 CD21lo B 细胞中的作用 CCB疗法。 我们希望这些研究将为识别以下自身免疫风险增加提供一个简单的标记 联合检查点疗法。了解 B 细胞的变化、定义其抗原靶点以及 T 细胞的作用 诱导这些 B 细胞变化的细胞也可能有助于确定预防和治疗的新途径和目标。 联合检查点阻断疗法后治疗 IRAE。

PROJECT SUMMARY Combination checkpoint blockade (CCB) therapy with anti-CTLA4 and anti-PD1 antibodies leads to high rates of tumor regression and has been approved by the FDA for upfront treatment of patients with advanced melanoma and is currently being evaluated in other tumors. Unfortunately, CCB also leads to high rates of immune-related adverse events (IRAEs), with over half of the treated patients experiencing grade 3-4 IRAEs leading to discontinuation of therapy in over a third of patients. Hence, development of IRAEs remain a major obstacle to optimal application of combination checkpoint blockade in human cancer. From a practical perspective, it would be highly desirable if patients at increased risk for the development of autoimmunity could be identified before clinical toxicity and the risk of autoimmunity reduced by preemptive intervention, without affecting clinical efficacy. This application builds on our recent studies to evaluate treatment-induced changes in immune cells that correlate with the risk of development of IRAEs. In these studies, we have observed that CCB therapy leads to a distinct pattern of changes in B cells which preceded and correlated with both the frequency and timing of IRAEs. In contrast, treatment-induced proliferation in circulating CD4 or CD8 T cells or quantitative changes in other immune cells (NK cells, monocytes) did not correlate with or predict the development of IRAEs. We hypothesize that patients with early changes in B cells identify a cohort at high risk for the development of autoimmunity following CCB. Preclinical models have to date not recapitulated the spectrum of CCB-associated autoimmunity observed in the clinic, supporting the need for human studies. The specific aims are: Aim 1. To validate B cell changes as a biomarker for increased risk of IRAEs in melanoma patients receiving CCB therapy and to evaluate the long term effects of CCB therapy on B cell subsets and function compared to those observed in the context of naturally occurring autoimmunity. Aim 2. To identify antigenic targets of B cells expanded following CCB therapy and examine their ability to serve as antigen presenting cells. Aim 3. To examine the role of T helper subsets cells in the activation of CD21lo B cells in patients receiving CCB therapy. We hope these studies will provide a simple marker for identifying increased risk for autoimmunity following combination checkpoint therapy. Understanding B cell changes, defining their antigenic targets and the role of T cells in inducing these B cell changes may also help to identify new pathways and targets for prevention and treatment of IRAEs following combination checkpoint blockade therapy.