CAR-Ts redirected against the Thomsen-Friedenreich antigen CD176 mediate specific elimination of malignant cells from leukemia and solid tumors
Dragon, Anna Christina (Hannover Medical School)
Beermann, Luca Marie (Hannover Medical School)
Umland, Melina (Hannover Medical School)
Bonifacius, Agnes (Hannover Medical School)
Malinconico, Chiara (Hannover Medical School)
Ruhl, Louisa (Hannover Medical School)
Kehler, Patrik (Glycotope GmbH)
Gellert, Johanna (Glycotope GmbH)
Weiß, Lisa (Glycotope GmbH)
Mayer-Hain, Sarah (Glycotope GmbH)
Zimmermann, Katharina (Hannover Medical School)
Riese, Sebastian (Hannover Medical School)
Thol, F. (Department of Hematology. Hannover Medical School)
Beutel, Gernot (Hannover Medical School)
Maecker-Kolhoff, B. (Department of Pediatric Hematology and Oncology. Hannover Medical School)
Yamamoto, Felicitas (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Blasczyk, Rainer (Hannover Medical School)
Schambach, Axel (Hannover Medical School)
Hust, Michael (Department of Medical Biotechnology. Technical University of Braunschweig)
Hudecek, Michael (Department of Internal Medicine II. University Hospital of Würzburg)
Eiz-Vesper, Britta (Hannover Medical School)
Universitat Autònoma de Barcelona

Fecha:	2023
Resumen:	Introduction: Chimeric antigen receptor-engineered T cells (CAR-Ts) are investigated in various clinical trials for the treatment of cancer entities beyond hematologic malignancies. A major hurdle is the identification of a target antigen with high expression on the tumor but no expression on healthy cells, since "on-target/off-tumor" cytotoxicity is usually intolerable. Approximately 90% of carcinomas and leukemias are positive for the Thomsen-Friedenreich carbohydrate antigen CD176, which is associated with tumor progression, metastasis and therapy resistance. In contrast, CD176 is not accessible for ligand binding on healthy cells due to prolongation by carbohydrate chains or sialylation. Thus, no "on-target/off-tumor" cytotoxicity and low probability of antigen escape is expected for corresponding CD176-CAR-Ts. Methods: Using the anti-CD176 monoclonal antibody (mAb) Nemod-TF2, the presence of CD176 was evaluated on multiple healthy or cancerous tissues and cells. To target CD176, we generated two different 2 generation CD176-CAR constructs differing in spacer length. Their specificity for CD176 was tested in reporter cells as well as primary CD8 T cells upon co-cultivation with CD176 tumor cell lines as models for CD176 blood and solid cancer entities, as well as after unmasking CD176 on healthy cells by vibrio cholerae neuraminidase (VCN) treatment. Following that, both CD176-CARs were thoroughly examined for their ability to initiate target-specific T-cell signaling and activation, cytokine release, as well as cytotoxicity. Results: Specific expression of CD176 was detected on primary tumor tissues as well as on cell lines from corresponding blood and solid cancer entities. CD176-CARs mediated T-cell signaling (NF-κB activation) and T-cell activation (CD69, CD137 expression) upon recognition of CD176 cancer cell lines and unmasked CD176, whereby a short spacer enabled superior target recognition. Importantly, they also released effector molecules (e. g. interferon-γ, granzyme B and perforin), mediated cytotoxicity against CD176 cancer cells, and maintained functionality upon repetitive antigen stimulation. Here, CD176L-CAR-Ts exhibited slightly higher proliferation and mediator-release capacities. Since both CD176-CAR-Ts did not react towards CD176 control cells, their response proved to be target-specific. Discussion: Genetically engineered CD176-CAR-Ts specifically recognize CD176 which is widely expressed on cancer cells. Since CD176 is masked on most healthy cells, this antigen and the corresponding CAR-Ts represent a promising approach for the treatment of various blood and solid cancers while avoiding "on-target/off-tumor" cytotoxicity.
Nota:	This research was in part funded by: "From CARs to TRUCKs: Induction of a concerted anti-tumor immune response by engineered T cells" (Deutsche Krebshilfe/German Cancer Aid-Priority Program in Translational Oncology #111975), "The Thomsen-Friedenreich antigen CD176: New target of chimeric antigen receptor (CAR)-modified immune cells in adoptive cancer immunotherapy" (Deutsche Kinderkrebsstiftung, Projekt DKS 2020.17), and Glycotope GmbH. Acknowledgments
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	CD176 ; Thomsen-Friedenreich antigen ; pan-tumor antigen ; carbohydrate antigen ; CAR-T cell therapy ; immunotherapy ; cancer ; solid tumors
Publicado en:	Frontiers in immunology, Vol. 14 (2023) , p. 1219165, ISSN 1664-3224

DOI: 10.3389/fimmu.2023.1219165
PMID: 37915564

16 p, 3.4 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
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