哺乳动物的免疫系统由两个不同的臂组成,非特异性先天和更具体的适应性,先天性免疫反应作为第一道防线和保护,启动并放大随后的适应性反应。在这种二元免疫相互作用的基础上,通过检查点抑制剂(CI)刺激T细胞,绕过先天的参与,似乎可能产生次优或不完全的抗癌免疫力,鉴于效果或反应的成功诱导取决于双向先天/适应性协调。的确,大多数患者-70%-80%,不要对CI做出回应,如果拒绝或延迟获得更最佳的标准疗法,而支持无效或仅勉强有效的抗PD-1/PD-L1治疗,则这可能是有问题的。因此,与CI(或其他T细胞毒性诱导剂)结合刺激先天免疫反应有可能使免疫系统“完整”,从而增强和扩大PD-1/PD-L1抑制剂的抗肿瘤活性,例如,在相对非免疫原性或“冷”肿瘤类型中。一个关键的先天巨噬细胞免疫检查点和药物靶标是抗吞噬和自身CD47-SIRPα途径的标记,它被癌细胞用来介导逃避免疫介导的清除和检查点抑制。这篇综述总结了关键的CD47拮抗剂在临床试验中的地位。包括生物制剂,Hu5F9-G4(5F9),TTI-621和ALX148,以及小分子,RRx-001,目前正在进行3期临床试验,以前没有纳入CD47-SIRPα综述,关注生物制剂。Hu5F9-G4(5F9),选择TTI-621、ALX148和RRx-001作为具有潜在有希望的数据的化合物,其在临床开发中取得了最大进展。
The mammalian immune system consists of two distinct arms, nonspecific innate and more specific adaptive, with the innate immune response as the first line of defense and protection, which primes and amplifies subsequent adaptive responses. On the basis of this binary immune interplay, stimulation of T cells through checkpoint inhibitors (CIs), which bypasses innate involvement, seems likely to engender suboptimal or incomplete anticancer immunity, given that the successful induction of effect or responses depends on two-way innate/adaptive coordination. Indeed, the majority of patients-70%-80%, do not respond to CIs, which is potentially problematic if access to more optimal standard therapies is withheld or delayed in favor of ineffective or only marginally effective anti-PD-1/PD-L1 treatment. Therefore, stimulation of the innate immune response in combination with CIs (or other inducers of T cell cytotoxicity) has the potential to make the immune system \"whole\" and thereby to enhance and broaden the anti-tumor activity of PD-1/PD-L1 inhibitors for example, in relatively nonimmunogenic or \"cold\" tumor types. A critical innate macrophage immune checkpoint and druggable target is the antiphagocytic and \"marker of self\" CD47-SIRPα pathway, which is co-opted by cancer cells to mediate escape from immune-mediated clearance and checkpoint inhibition. This
review summarizes the status of key CD47
antagonists in clinical trials, including the biologics, Hu5F9-G4 (5F9), TTI-621, and ALX148, as well as the small molecule, RRx-001, now in a Phase 3 clinical trial, which has not been previously included in CD47-SIRPα reviews focused on biologics. Hu5F9-G4 (5F9), TTI-621, ALX148, and RRx-001 are chosen as compounds with potentially promising data that have advanced the farthest in clinical development.