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

总结 使用抗CTLA-4和抗PD-1 mAb的组合疗法已经成为最有效和最有效的治疗方法。 持久的癌症免疫疗法。然而，与联合用药相关的自身免疫性不良反应 治疗相当严重，50-90%的黑素瘤患者发展为3级和4级 免疫治疗相关副作用。癌症免疫治疗的一个主要挑战是如何减少不良反应。 在不影响治疗效果的情况下，这在一定程度上与以下事实有关： 联合治疗加重irAE的机制还不清楚。为了解决这个问题， 我们已经开发了一种新的模型，其中抗小鼠PD-1联合 伊匹单抗或曲美珠单抗概括了临床上观察到的严重irAE。重要的是，不同的抗- 在该临床前模型中，人CTLA 4抗体在irAE中显著不同。我们进行了广泛的 初步研究阐明了irAE倾向性抗体与非倾向性抗体的分子基础， 抗体介导的膜相关CTLA-4的降解是易发生irAE的抗体的主要特征。 同时，长期以来已经确定可溶性CTLA-4（sCTLA 4）分子对抗肿瘤具有保护性， 小鼠的自身免疫性疾病。我们已经获得的数据表明， sCTLA 4和irAE的临床应用。我们进一步建立了高结合与可溶性 CTLA 4蛋白和人CTLA 4KI小鼠中irAE的严重程度。根据这些意想不到的观察， CTLA 4-Fc（阿巴西普，作为Orencia销售）对自身免疫性疾病的强治疗效果 包括irAE，我们假设细胞表面和sCTLA-4都能提供抗irAE的保护， 逃避irAE诱导的抗CTLA-4抗体清除的sCTLA-4是一种潜在的治疗方法， 预防和治疗irAE。 我们的建议挑战了自身免疫和癌症免疫所基于的流行范式 相同的机制，因此内在联系。更重要的是，我们的工作将产生变革性的影响， 在免疫肿瘤学研究中，因为它可以为与大多数 有效的免疫疗法在临床上的应用。

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.