Co-expression of non-signaling CARs enhances EGFRvIII-specific CAR T-cell cytotoxicity against head and neck squamous cell carcinoma.
Zusammenfassung: Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat due to heterogeneous antigen expression and an immunosuppressive tumor microenvironment. The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific splice form with no detectable protein expression in normal tissues. Nevertheless, its low and often heterogeneous expression in HNSCC has limited its utility as target antigen for immunological therapies using chimeric antigen receptor (CAR) T-cells. In contrast, full-length EGFR is frequently overexpressed in HNSCC, but its expression in normal tissues prevents its use as a directly activating CAR target. Thus, we investigated here whether EGFR can instead provide additional target antigen engagement as a non-signaling CAR (nsCAR) for EGFRvIII CARs. The nsCAR was derived from Cetuximab, an EGFR-binding monoclonal antibody whose epitope is retained in EGFRvIII and was co-expressed with different EGFRvIII-specific signaling CAR to investigate whether additional receptor engagement could enhance target-cell recognition and cytotoxicity.
Autoren: Kathleen Grueter, Nicole Sander, Luisa Coen, Saskia Hüsken, Eileen Kleinfelder, Corinna Haist, Franziska Blaeschke, Kathrin Scheckenbach, Cornelia Monzel, Helmut Hanenberg, Constanze Wiek
Veröffentlicht: Sep 2026 / Journal: BMC cancer
The ITCC-P4 PDX Platform Enables Preclinical Testing of Pediatric Cancers.
Zusammenfassung: Cancer is the leading cause of disease-related deaths among children in high-income countries. Tumor heterogeneity and the lack of mechanism of action-based therapeutic options are key challenges to overcome to improve the survival of pediatric patients with cancer. To address these challenges, we formed the European Union-Innovative Medicines Initiative 2 (EU-IMI2) funded public-private partnership "Innovative Therapies for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform" (ITCC-P4), which built a large repertoire of patient-derived xenograft (PDX) models representing all major high-risk solid pediatric cancer types for in vivo drug testing. A total of 353 PDX models were established from diagnostic and relapsed pediatric cancers and molecularly characterized, together with matched germline/tumor samples. Serial PDX models were also established, spanning diagnostic/posttreatment, primary/relapse, and metastasis-derived pairs. Proof-of-concept in vivo drug screening data in neuroblastoma and rhabdomyosarcoma models identified potential predictive biomarkers for targeted therapy. Molecular data from the PDX models, accessible at https://r2platform.com/itcc-p4, allowed the selection of models for preclinical testing based on oncogenic drivers and/or potential biomarkers. Operated by a nonprofit entity, this sustainable platform aids academic and industrial researchers in developing and prioritizing innovative therapies for pediatric cancer.
Autoren: Aniello Federico, Apurva Gopisetty, Didier Surdez, Yasmine Iddir, Robert J Autry, Joshua J Waterfall, Elnaz Saberi-Ansari, Charles Bobin, Stelly Ballet, Gaelle Pierron, Justyna A Wierzbinska, Andreas Schlicker, Martin Sill, Richard Volckmann, Danny A Zwijnenburg, Alan Mackay, Sakina Zaïdi, Alexandra Saint-Charles, Norman Mack, Benjamin Schwalm, Sebastian Brabetz, Lena Weiser, Ivo Buchhalter, Christopher Previti, Anna-Lisa Böttcher, Fatima Iradier, Eva-Maria Rief, David T W Jones, Olaf Witt, Frank Westermann, Till Milde, Angelika Eggert, Nicole Huebener, Johannes H Schulte, Sara Colombetti, Louis Chesler, Elizabeth R Tucker, Alaide Morcavallo, Federica Lorenzi, Heinrich Kovar, Jan-Henning Klusmann, Klaus-Michael Debatin, Simon Bomken, Christina D Guttke, Petra Hamerlik, Maureen M Hattersley, Michelle Garcia, Frédéric Colland, Ashley Strougo, Pablo Aviles, Michal Zapotocky, David Sumerauer, Johannes Gojo, Walter Berger, Daniela Lötsch-Gojo, Julia Schueler, Emily J Girard, James M Olson, Beat W Schäfer, Marco Wachtel, Jan J Molenaar, Biljana Dumevska, Elisabet Fernandez Potente, Chris Jones, Angel M Carcaboso, Emilie Indersie, Stefano Cairo, Katia Scotlandi, Maria Cristina Manara, Lorena Landuzzi, Angela Di Giannatale, Patrizia Gasparini, Massimo Moro, Dennis Gürgen, Jens Hoffmann, Maria Eugenia Marques da Costa, Birgit Geoerger, Olivier Delattre, David J Shields, Hubert N Caron, Gilles Vassal, Louis F Stancato, Stefan M Pfister, Natalie Jäger, Jan Koster, Marcel Kool, Gudrun Schleiermacher
Veröffentlicht: Oct 2026 / Journal: Cancer research