■嵌合抗原受体T(CAR-T)细胞疗法在血液肿瘤的治疗中取得了显著的成功。然而,鉴于实体瘤的独特特征,特别是异质性,代谢侵略性,肿瘤微环境(TME)中的免疫细胞较少,CAR-T细胞在实体瘤中的实际应用仍然是一个具有挑战性的问题.同时,尽管抗PD-1单克隆抗体(mAb)已显示出临床疗效,大多数mAb对实体瘤的临床益处也有限,这主要是由于与TME中缺乏免疫细胞相关的问题.因此,靶向免疫活性细胞浸润到TME中可以产生对mAb的协同功效。
■我们提出了一种实体瘤治疗的组合策略,它结合装甲T细胞在表面上表达Fc-γ受体I(FcγRI)片段,用于靶向治疗上有用的单克隆抗体的各种肿瘤。选择CD20和HER-2作为目标,我们通过流式细胞术表征了联合药物的体内外功效和潜在机制,ELISA等方法。
■装甲T细胞与利妥昔单抗和帕妥珠单抗的相应抗体的组合和预处理发挥了深远的抗肿瘤作用,这被证明是由协同产生的抗体依赖性细胞毒性(ADCC)效应介导的。同时,mAb能够通过在细胞来源的异种移植物(CDX)模型中对TME的浸润进行预处理而携带铠装T细胞。
■该组合策略显示出由于抗体剂量的减少而使安全性谱显著增加。更重要的是,目前的策略可能是广谱癌症治疗的通用工具,简单配对的工程T细胞和常规抗体。
UNASSIGNED: Chimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of solid tumors, particularly heterogeneity, metabolic aggressiveness, and fewer immune cells in tumor microenvironment (TME), the practical utility of CAR-T cells for solid tumors remains as a challenging issue. Meanwhile, although anti-PD-1 monoclonal antibody (mAb) has shown clinical efficacy, most mAbs also show limited clinical benefits for solid tumors due mainly to the issues associated with the lack of immune cells in TME. Thus, the infiltration of targeted immunological active cells into TME could generate synergistic efficacy for mAbs.
UNASSIGNED: We present a combinational strategy for solid tumor treatment, which combines armored-T cells to express Fc-gamma receptor I (FcγRI) fragment on the surfaces for targeting various tumors with therapeutically useful mAbs. Choosing CD20 and HER-2 as the targets, we characterized the in vitro and in vivo efficacy and latent mechanism of the combination drug by using flow cytometry, ELISA and other methods.
UNASSIGNED: The combination and preprocessing of armored T-cells with corresponding antibody of Rituximab and Pertuzumab exerted profound anti-tumor effects, which is demonstrated to be mediated by synergistically produced antibody-dependent cellular cytotoxicity (ADCC) effects. Meanwhile, mAb was able to carry armored-T cell by preprocessing for the infiltration to TME in cell derived xenograft (CDX) model.
UNASSIGNED: This combination strategy showed a significant increase of safety profiles from the reduction of antibody doses. More importantly, the present strategy could be a versatile tool for a broad spectrum of cancer treatment, with a simple pairing of engineered T cells and a conventional antibody.