Miltenyi Biotec GmbH, R&D, Bergisch Gladbach, North Rhine-Westphalia, Germany.
University Medical Center Göttingen, Clinic for Hematology and Medical Oncology, Göttingen, Lower Saxony, Germany.
Nat Commun. 2021 Mar 5;12(1):1453. doi: 10.1038/s41467-021-21774-4.
A major roadblock prohibiting effective cellular immunotherapy of pancreatic ductal adenocarcinoma (PDAC) is the lack of suitable tumor-specific antigens. To address this challenge, here we combine flow cytometry screenings, bioinformatic expression analyses and a cyclic immunofluorescence platform. We identify CLA, CD66c, CD318 and TSPAN8 as target candidates among 371 antigens and generate 32 CARs specific for these molecules. CAR T cell activity is evaluated in vitro based on target cell lysis, T cell activation and cytokine release. Promising constructs are evaluated in vivo. CAR T cells specific for CD66c, CD318 and TSPAN8 demonstrate efficacies ranging from stabilized disease to complete tumor eradication with CD318 followed by TSPAN8 being the most promising candidates for clinical translation based on functionality and predicted safety profiles. This study reveals potential target candidates for CAR T cell based immunotherapy of PDAC together with a functional set of CAR constructs specific for these molecules.
有效进行胰腺导管腺癌（PDAC）的细胞免疫治疗的主要障碍是缺乏合适的肿瘤特异性抗原。为了解决这一挑战，我们结合流式细胞术筛选、生物信息表达分析和循环免疫荧光平台，从 371 种抗原中鉴定出 CLA、CD66c、CD318 和 TSPAN8 作为候选靶标，并为这些分子生成了 32 种 CAR。基于靶细胞裂解、T 细胞激活和细胞因子释放，在体外评估 CAR T 细胞的活性。对有前途的构建体进行体内评估。针对 CD66c、CD318 和 TSPAN8 的 CAR T 细胞表现出从稳定疾病到完全肿瘤消除的疗效，其中 CD318 后是 TSPAN8 是基于功能和预测安全性概况最有前途的临床转化候选者。这项研究揭示了用于 PDAC 的 CAR T 细胞免疫治疗的潜在靶标候选物，以及针对这些分子的功能齐全的 CAR 构建体集。
