Kristmann Beate, Werchau Niels, Suresh Lakshmi, Pezzuto Elisabeth L, Scheuermann Sophia, Krost Simon, Schilbach Karin, Moustafa-Oglou Moustafa, Mast Anna-Sophia, Droste Miriam, Felsberger André, Kiefer Lukas, Abramowski Pierre, Zender Lars, Mittelstaet Joerg, Seitz Christian M
Department of General Pediatrics, Hematology and Oncology, University Children's Hospital Tuebingen, Tübingen, Germany.
Institute for Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tübingen, Germany.
J Hematol Oncol. 2025 Jul 28;18(1):76. doi: 10.1186/s13045-025-01729-8.
Survival rates in Small Cell Lung Cancer (SCLC) remain dismal, posing a huge medical need for novel therapies. T-cells, engineered to express chimeric antigen receptors (CAR-T) have demonstrated clinical activity against a variety of haematological malignancies. Yet, efficacy against solid tumour entities remains limited.
In this study, we investigated the expression of CD276 (B7-H3), an immune checkpoint molecule and promising target antigen for CAR-T therapy in SCLC, at the RNA and protein level. We further developed novel Fab-based adapter molecules (AM) targeting CD276 and optimized our previously established modular Adapter CAR-T (AdCAR-T) platform as well as AM dosing schemes.
CD276 is broadly expressed across SCLC subtypes, representing a promising target for CAR-T therapy. We describe that T-cell activation and CAR-signalling induces CD276-expression on CAR-T, resulting in CD276-dependent fratricide, limiting anti-CD276-CAR-T expansion and activity. The AdCAR-T platform allows CAR-T expansion in absence of CD276 targeting. Novel CD276 targeted AMs demonstrate potent in vitro and in vivo activity against SCLC. Intermittent AM-dosing allows functional persistence of AdCAR-T in vivo in contrast to CD276-targeted conventional CAR-T. AdCAR-T in vivo expansion and activity is further promoted by introducing activation-induced, AM remote controlled, IL-18 secretion into the AdCAR-T design.
We identified CD276 as a promising target antigen, uniformly expressed in SCLC and demonstrate the therapeutic potential of novel anti-CD276 Fab-based AM in combination with optimized, IL-18 armoured AdCAR-T.
小细胞肺癌（SCLC）的生存率仍然很低，对新型疗法存在巨大的医学需求。经过基因工程改造以表达嵌合抗原受体（CAR-T）的T细胞已显示出对多种血液系统恶性肿瘤的临床活性。然而，对实体瘤的疗效仍然有限。
在本研究中，我们在RNA和蛋白质水平上研究了免疫检查点分子CD276（B7-H3）的表达，其是SCLC中CAR-T治疗有前景的靶抗原。我们进一步开发了靶向CD276的新型基于Fab的衔接分子（AM），并优化了我们先前建立的模块化衔接子CAR-T（AdCAR-T）平台以及AM给药方案。
CD276在SCLC各亚型中广泛表达，是CAR-T治疗的一个有前景的靶点。我们描述了T细胞活化和CAR信号传导诱导CAR-T上CD276的表达，导致CD276依赖性自相残杀，限制了抗CD276-CAR-T的扩增和活性。AdCAR-T平台允许在不靶向CD276的情况下进行CAR-T扩增。新型靶向CD276的AMs在体外和体内均显示出对SCLC的有效活性。与靶向CD276的传统CAR-T相比，间歇性AM给药可使AdCAR-T在体内保持功能持久性。通过将激活诱导的、AM远程控制的IL-18分泌引入AdCAR-T设计中，进一步促进了AdCAR-T在体内的扩增和活性。
我们确定CD276是一个有前景的靶抗原，在SCLC中均匀表达，并证明了新型抗CD276 Fab基AM与优化的、IL-18武装的AdCAR-T联合使用的治疗潜力。
