Targeted activation of autoimmune checkpoints in B cell malignancies

癌症的靶向治疗通常集中在将致癌信号抑制在最低限度以下的药物 生存和扩散所需的门槛。在这里，我们提出了一种克服耐药性的新策略 在B细胞恶性肿瘤中，靶向激活自身免疫检查点(AIC)以去除 自身反应性B细胞。由于B细胞库需要审查自身反应克隆，B细胞 它们的信号要求与其他类型的细胞有根本的不同。与其他类型的癌症不同，B细胞 恶性肿瘤是由自身反应性过度活跃的信号引起的克隆性缺失的唯一易感性 B细胞受体(BCR)。我们小组最近的三项研究表明，靶向激活AIC是可以实现的 通过最大阈值以上的bcr信号的药物过度激活(Chen等人，《自然》2015； Shojaee等人，癌症细胞2015；Shojaee等人，《自然医学》2016)。因此，定向AIC激活可以 用于根除抗药性B细胞白血病和淋巴瘤克隆。 基于这些和其他发现，我们提出了三个目标来验证靶向自身免疫检查点(AIC)- 激活作为治疗人类B细胞恶性肿瘤的新概念： 1.这一提议包括一个机械目标，该目标基于新的观察，即检查站以保障 自身免疫性疾病在B细胞恶性肿瘤中仍然起作用。这一目标探索了AIC-激活如何 在B细胞恶性肿瘤中可以可靠地实现，以及AIC激活如何导致细胞死亡。 2.分层目标将确定可能对以下疾病最敏感的疾病亚型和患者群体 AIC-激活并阐明不同治疗反应的生物学基础。 3.治疗目标将通过优先考虑特定的靶向过度激活来完善治疗概念 通过探索与已有的治疗药物的组合，来研究bcr途径的成分。

Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold needed for survival and proliferation. Here, we propose a novel strategy to overcome drug-resistance in B cell malignancies based on targeted activation of an autoimmunity checkpoint (AIC) for removal of autoreactive B cells. Owing to the necessity of the B cell repertoire to censor autoreactive clones, B cells fundamentally differ in their signaling requirements from other cell types. Unlike other types of cancer, B cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive B cell receptor (BCR). Three recent studies from our group showed that targeted AIC-activation is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (Chen et al., Nature 2015; Shojaee et al., Cancer Cell 2015; Shojaee et al., Nature Med 2016). Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant B cell leukemia and lymphoma clones. Based on these and other findings, we propose three Aims to validate targeted autoimmunity checkpoint (AIC)- activation as new concept for the treatment of human B cell malignancies: 1. This proposal includes a mechanistic Aim based on the novel observation that checkpoints to safeguard from autoimmunity disease are still functional in B cell malignancies. This Aim explores how AIC-activation can be reliably achieved in B cell malignancies and how AIC-activation leads to cell death. 2. The stratification Aim will identify disease subtypes and groups of patients that may be most responsive to AIC-activation and elucidate the biological basis of different treatment responses. 3. A therapeutic Aim will refine the treatment concept by prioritizing targeted hyperactivation of specific components of the BCR pathway and by exploring combinations with established treatment agents.