The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Gastroenterology. 2023 Nov;165(5):1219-1232. doi: 10.1053/j.gastro.2023.06.037. Epub 2023 Jul 26.
BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs).
We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE.
AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3 T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures.
Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.
双特异性 T 细胞衔接器（BiTE）免疫疗法已在多种肿瘤适应证中显示出临床活性，但它在肿瘤微环境中的影响尚不清楚。CLDN18.2 在包括胃癌（GC）和胰腺导管腺癌（PDAC）在内的实体瘤中过度表达，这两种肿瘤的特征是存在免疫抑制细胞，包括调节性 T 细胞（Tregs）和少数效应 T 细胞（Teffs）。
我们评估了 CLDN18.2 靶向半衰期延长（HLE）BiTE 分子 AMG 910 在 GC 和 PDAC 临床前模型中的活性，并在存在 CLDN18.2-HLE-BiTE 的情况下将 Tregs 和 Teffs 共培养。
AMG 910 在 GC 和 PDAC 细胞系中诱导出强大、特异的细胞毒性。在 GSU 和 SNU-620 GC 异种移植模型中，AMG 910 使人类 CD3 T 细胞与肿瘤细胞结合，导致显著的抗肿瘤活性。AMG 910 单药治疗与程序性死亡-1（PD-1）抑制剂联合应用，可抑制原位 Panc4.14 PDAC 模型中的肿瘤生长并提高生存率。此外，Treg 输注增强了 AMG 910 在 Panc4.14 模型中的抗肿瘤疗效。在 PDAC 的同基因 KPC 模型中，用小鼠替代 CLDN18.2-HLE-BiTE（muCLDN18.2-HLE-BiTE）治疗或与抗 PD-1 抗体联合治疗显著抑制肿瘤生长。用 muCLDN18.2-HLE-BiTE 治疗的 KPC 肿瘤小鼠分离的 Tregs 显示出 T 细胞抑制活性降低和 Teff 细胞毒性活性增强，与 I 型细胞因子产生增加和 Teff 基因特征表达相关。
我们的数据表明，BiTE 分子治疗将 Treg 功能从免疫抑制转化为免疫增强，导致免疫“冷”肿瘤的抗肿瘤活性。
