Preserving CTLA-4 immune checkpoint for safer and more effective cancer immunotherapy

摘要 抗CTLA-4和抗PD-1单抗联合治疗已成为最有效的和 持久的癌症免疫疗法。然而，与联合使用相关的自身免疫不良反应 治疗要严重得多，50%-90%的黑色素瘤患者发展为3级和4级 免疫治疗相关不良反应。癌症免疫治疗的一大挑战是如何减少不良反应 在不影响疗效的情况下，联合治疗的效果。这在一定程度上与以下事实有关 联合治疗加重IRAE的机制尚不清楚。为了解决这个问题， 我们已经开发出一种新的模型，在该模型中，抗鼠PD-1联合治疗 Ipiimumab或Tremelizumab概括了临床上观察到的严重的IRAE。重要的是，不同的反- 在这个临床前模型中，人类CTLA4抗体在IRAE中有很大的不同。我们已经开展了广泛的 初步研究阐明了IRAE倾向抗体与非倾向抗体的分子基础，并表明 抗体介导的膜相关CTLA-4的降解是IRAE倾向抗体的主要特征。 同时，很早就证实可溶性CTLA-4(sCTLA-4)分子具有保护作用。 小鼠的自身免疫性疾病。我们已经获得的数据表明，这些水平之间存在很强的相关性 SCTLA4和IRAE在诊所里。我们进一步建立了高结合力与可溶性之间的显著相关性 CTLA4蛋白与人CTLA4KI小鼠IRAE的严重程度基于这些意想不到的观察和 CTLA4-FC(abatacept，奥伦西亚)对自身免疫性疾病的强大疗效 包括IRAE，我们假设细胞表面和sCTLA-4都提供了对IRAE的保护，并且 通过IRAE诱导的抗CTLA-4抗体逃避清除的sCTLA4是一种潜在的治疗方法 IRAE的防治。 我们的建议挑战了自身免疫和癌症免疫所依据的主流模式 同样的机制，因此有着内在的联系。更重要的是，我们的工作将产生革命性的影响 在免疫肿瘤学研究中，因为它可以预防和治疗与大多数 临床上使用的有效免疫疗法。

Summary Combination therapy with anti-CTLA-4 and anti-PD-1 mAbs has emerged as the most potent and durable cancer immunotherapy. However, the autoimmune adverse effect associated with the combination therapy is considerably more severe, with 50-90% of melanoma patients developing grade 3 and 4 immunotherapy-related adverse effect. A major challenge in cancer immunotherapy is how to reduce adverse effects of the combination therapy without affecting therapeutic efficacy. This is in part related to the fact that the mechanism by which combination therapy exacerbate irAE is not well understood. To address this issue, we have developed a novel model in which combination therapy with anti-mouse PD-1 in conjunction with either Ipilimumab or Tremelizumab recapitulates the severe irAE observed in clinic. Importantly, different anti- human CTLA4 antibodies differ dramatically in irAE in this preclinical model. We have carried out extensive preliminary studies to elucidate the molecular basis of irAE-prone vs non-prone antibodies and have shown the antibody-mediated degradation of membrane-associated CTLA-4 as a major feature of irAE-prone antibodies. Meanwhile, it has long been established that soluble CTLA-4 (sCTLA4) molecule is protective against autoimmune diseases in the mice. We have obtained data that showed strong correlation between the levels of sCTLA4 and irAE in the clinic. We further established a striking correlation between high binding to soluble CTLA4 protein and the severity of irAE in human CTLA4KI mice. Based on these unexpected observations and the strong therapeutic effect of CTLA4-Fc (Abatacept, marketed as Orencia) for autoimmune diseases including irAE, we hypothesize that both cell surface and sCTLA-4 confers protection against irAE and that sCTLA4 that evades clearance by irAE-inducing anti-CTLA-4 antibodies is a potential therapeutic for prevention and treatment of irAE. Our proposal challenges the prevailing paradigm that autoimmunity and cancer immunity are based on the same mechanism and thus intrinsically linked. More importantly, our work will have a transforming impact in immune-oncology research, as it may offer prophylactic and treatment for irAEs associated with the most effective immunotherapy in use in the clinic.