Kwan Byron H, Zhu Eric F, Tzeng Alice, Sugito Harun R, Eltahir Ahmed A, Ma Botong, Delaney Mary K, Murphy Patrick A, Kauke Monique J, Angelini Alessandro, Momin Noor, Mehta Naveen K, Maragh Alecia M, Hynes Richard O, Dranoff Glenn, Cochran Jennifer R, Wittrup K Dane
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
J Exp Med. 2017 Jun 5;214(6):1679-1690. doi: 10.1084/jem.20160831. Epub 2017 May 4.
Certain RGD-binding integrins are required for cell adhesion, migration, and proliferation and are overexpressed in most tumors, making them attractive therapeutic targets. However, multiple integrin antagonist drug candidates have failed to show efficacy in cancer clinical trials. In this work, we instead exploit these integrins as a target for antibody Fc effector functions in the context of cancer immunotherapy. By combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity. Functional integrin antagonism does not contribute significantly to efficacy; rather, this therapy recruits both an innate and adaptive immune response, as deficiencies in either arm result in reduced tumor control. Administration of this integrin-targeted immunotherapy together with an anti-PD-1 antibody further improves responses and predominantly results in cures. Overall, this well-tolerated therapy achieves tumor specificity by redirecting inflammation to a functional target fundamental to tumorigenic processes but expressed at significantly lower levels in healthy tissues, and it shows promise for translation.
某些RGD结合整合素是细胞黏附、迁移和增殖所必需的,且在大多数肿瘤中过度表达,这使其成为有吸引力的治疗靶点。然而,多种整合素拮抗剂候选药物在癌症临床试验中未能显示出疗效。在这项研究中,我们转而将这些整合素作为癌症免疫治疗背景下抗体Fc效应功能的靶点。通过将工程化小鼠血清白蛋白/IL-2融合蛋白与整合素结合肽的Fc融合蛋白(2.5F-Fc)联合给药,在三种同基因小鼠肿瘤模型中实现了显著的生存期改善,包括产生具有保护性免疫的完全缓解。功能性整合素拮抗作用对疗效的贡献不大;相反,这种疗法募集了先天性和适应性免疫反应,因为任何一方的缺陷都会导致肿瘤控制能力下降。将这种整合素靶向免疫疗法与抗PD-1抗体联合使用可进一步改善反应,并主要导致治愈。总体而言,这种耐受性良好的疗法通过将炎症重定向到肿瘤发生过程的一个功能性靶点来实现肿瘤特异性,该靶点在健康组织中的表达水平显著较低,并且显示出转化应用的前景。