B cells in autoimmunity following checkpoint blockade therapy

项目总结 联合检查点阻断(CCB)和抗CTLA4和抗PD1抗体导致高发生率 肿瘤消退，并已被FDA批准用于晚期癌症患者的早期治疗 黑色素瘤，目前正在对其他肿瘤进行评估。不幸的是，建行也导致了较高的 免疫相关不良事件(IRAE)，超过一半的接受治疗的患者经历3-4级IRAE 导致超过三分之一的患者停止治疗。因此，IRAE的发展仍然是一个主要问题 联合检查点阻断在人类癌症中最佳应用的障碍。从一个实用的 从角度来看，如果自身免疫发展风险增加的患者能够 在临床毒性和自身免疫风险通过先发制人的干预降低之前确定，而不是 影响临床疗效的。这一应用程序建立在我们最近的研究基础上，以评估治疗引起的 与IRAE发病风险相关的免疫细胞。在这些研究中，我们观察到建行 治疗导致了B细胞的一种明显的变化模式，这种模式发生在频率之前，并与这两种频率相关 和IRAE的时机。相比之下，治疗诱导循环中的CD4或CD8T细胞增殖或数量 其他免疫细胞(NK细胞、单核细胞)的变化与IRAE的发展无关，也不预测IRAE的发展。 我们假设，早期B细胞变化的患者发现了一个高危人群，他们可能会发展为 CCB后的自身免疫力。临床前模型到目前为止还没有概括出与CCB相关的光谱 在临床上观察到了自身免疫，支持了人体研究的必要性。具体目标是： 目的1.验证B细胞变化作为黑色素瘤患者接受IRAE治疗风险增加的生物标志物 并评价CCB治疗对B细胞亚群和功能的远期影响。 在自然发生的自身免疫的背景下观察到的那些。 目的2.鉴定CCB治疗后扩增的B细胞的抗原靶细胞，并检测它们的能力 作为抗原提呈细胞。 目的3.检测T辅助细胞亚群在CD21lo B细胞活化中的作用 CCB疗法。 我们希望这些研究将提供一个简单的标记物，用于确定以下自身免疫风险的增加 联合检查点疗法。了解B细胞的变化，确定其抗原靶点和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靶点 联合检查点阻断治疗后IRAEs的治疗。

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.