Inducible IL-12 or IL-18 secreting CAR T cells targeting the glyco-antigen CD176 exhibit potent activity against non-small cell lung cancer in preclinical models
Abstract To date, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide, underscoring the urgent need for new treatment options. The oncofetal carbohydrate CD176 is masked on healthy tissues but is present on a variety of cancer entities and is associated with cancer invasiveness and metastasis. In this study, we employed chimeric antigen receptor T cells (CAR-Ts) directed against CD176 for treatment of NSCLC. CD176-CAR-Ts were optimized with an additional inducible cassette encoding IL-18 (CD176-iIL18-TRUCKs) or IL-12 (CD176-iIL12-TRUCKs) to augment antitumor reactivity through autocrine and paracrine signaling. CD176-iIL18- and CD176-iIL12-TRUCKs eradicate NSCLC cells in a 3D tumor spheroid model and tissue slices derived from lung adenocarcinoma patients more potently than CD176-CAR-Ts. Administration of TRUCKs in a lung carcinoma xenograft mouse model results in partial or complete tumor eradication in all mice treated with CD176-iIL12-TRUCKs and in 50% of mice treated with CD176-iIL18-TRUCKs. This study highlights the potential of CD176 as a CAR-T-cell target and suggest CD176-CAR-Ts armored with IL-18 or IL-12 as promising new therapeutic approach for the treatment of NSCLC and several other CD176-positive cancer entities.
Authors
- Tonia Bargmann (ORCID: https://orcid.org/0000-0002-5170-4687)
- Rainer Blasczyk (ORCID: https://orcid.org/0000-0003-3875-3190)
- Lavinia Neubert (ORCID: https://orcid.org/0000-0003-4130-4185)
- Anna Christina Dragon (ORCID: https://orcid.org/0000-0002-5228-7627)
- Britta Eiz‐Vesper (ORCID: https://orcid.org/0000-0001-8378-3298)
- STEFAN J. DUBEL (ORCID: https://orcid.org/0000-0001-8811-7390)
- Armin C. Braun (ORCID: https://orcid.org/0000-0002-1142-1463)
- Axel Schambach (ORCID: https://orcid.org/0000-0003-2743-0070)
- Quentin Deveuve (ORCID: https://orcid.org/0000-0002-4803-2584)
- Justus Weber (ORCID: https://orcid.org/0000-0002-4919-952X)
- Agnes Bonifacius (ORCID: https://orcid.org/0000-0002-0112-967X)
- Hinrich Abken (ORCID: https://orcid.org/0000-0002-4302-3240)
- Johanna Gellert (ORCID: https://orcid.org/0009-0005-9518-9137)
- Michael Hudecek (ORCID: https://orcid.org/0000-0002-2280-2202)
- Melina Umland
- Chiara Malinconico (ORCID: https://orcid.org/0009-0009-6664-7636)
- Katharina Zimmermann (ORCID: https://orcid.org/0000-0003-0029-382X)
- Antonina Jana. Polzien (ORCID: https://orcid.org/0009-0007-0496-1545)
Institutions
- University of Würzburg (DE)
- Italian Institute of Technology (IT)
- Medizinische Hochschule Hannover (DE)
- Glycotope (Germany) (DE)
- Augenklinik Universitätsklinikum Würzburg (DE)
- Fraunhofer Institute for Toxicology and Experimental Medicine (DE)
- Universitätsklinikum Würzburg (DE)
- University of Regensburg (DE)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2026-09-22
- DOI
- https://doi.org/10.1158/2326-6066.cir-25-1399
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00