Kristmann, Beate and Werchau, Niels and Suresh, Lakshmi and Pezzuto, Elisabeth L. and Scheuermann, Sophia and Krost, Simon and Schilbach, Karin and Moustafa-Oglou, Moustafa and Mast, Anna-Sophia and Droste, Miriam and Felsberger, Andre and Kiefer, Lukas and Abramowski, Pierre and Zender, Lars and Mittelstaet, Joerg and Seitz, Christian M. (2025) Targeting CD276 with Adapter-CAR T-cells provides a novel therapeutic strategy in small cell lung cancer and prevents CD276-dependent fratricide. JOURNAL OF HEMATOLOGY & ONCOLOGY, 18 (1): 76. ISSN , 1756-8722
Full text not available from this repository. (Request a copy)Abstract
BackgroundSurvival 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.MethodsIn 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.ResultsCD276 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.ConclusionWe 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHIMERIC ANTIGEN RECEPTOR; IFN-GAMMA; TUMORS; B7-H3; SCLC; CD276; Immunotherapy; AdCAR-T; Fab-based adapter molecule; Fratricide; In vivo solid tumor targeting |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Apr 2026 10:02 |
| Last Modified: | 17 Apr 2026 10:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67684 |
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