TY  - JOUR
AU  - Reindl, Lisa Marie
AU  - Jalili, Lida
AU  - Bexte, Tobias
AU  - Harenkamp, Sabine
AU  - Thul, Sophia
AU  - Hehlgans, Stephanie
AU  - Wallenwein, Alina
AU  - Rothweiler, Florian
AU  - Cinatl, Jindrich
AU  - Michaelis, Martin
AU  - Bonig, Halvard
AU  - Gradhand, Elise
AU  - Vogler, Meike
AU  - Rödel, Franz
AU  - Wels, Winfried S
AU  - Ullrich, Evelyn
TI  - Precision targeting of rhabdomyosarcoma by combining primary CAR NK cells and radiotherapy.
JO  - Journal for ImmunoTherapy of Cancer
VL  - 13
IS  - 7
SN  - 2051-1426
CY  - London
PB  - BioMed Central
M1  - DKFZ-2025-01355
SP  - e011330
PY  - 2025
AB  - Background: Rhabdomyosarcoma (RMS) is the most common type of soft-tissue sarcoma in children, and it remains a challenging cancer with poor outcomes in high-risk and metastatic patients. This study reports the use of epidermal growth factor receptor (EGFR)-targeted chimeric antigen receptor (CAR) natural killer (NK) cells in combination with radiotherapy as a novel immunotherapeutic approach for RMS treatment.Methods: Primary human NK cells from healthy donors were engineered using lentiviral transduction to express a cetuximab-based EGFR-specific CAR. The ability of the engineered NK cells to lyse RMS cells was then assessed in vitro in RMS monolayers and spheroids, as well as against chemotherapy-resistant and primary patient-derived RMS cells. Migratory properties of NK cells were observed in a subcutaneous RMS xenograft model using in vivo imaging, and the efficacy of EGFR-CAR NK cells in combination with localized fractionated radiotherapy was analyzed.Results: Primary human EGFR-CAR NK cells demonstrated enhanced cytotoxicity against multiple RMS cell lines in both two-dimensional culture and three-dimensional spheroid models. Furthermore, EGFR-CAR NK cells were highly efficient against chemotherapy-resistant RMS cells and patient-derived samples. Importantly, EGFR-CAR NK cells also exhibited improved tumor homing compared with non-transduced NK cells in an in vivo RMS xenograft model. Notably, the combination of EGFR-CAR NK cell therapy with fractionated radiotherapy further enhanced NK cell infiltration into the tumor and reduced tumor growth.Conclusion: This study provides a proof-of-concept for EGFR-CAR NK cells as a promising immunotherapy for RMS, particularly when combined with radiotherapy to overcome barriers of solid tumors. This combinatorial approach may hold potential to improve outcomes for patients with RMS and other EGFR-expressing malignancies.
KW  - Humans
KW  - Animals
KW  - Rhabdomyosarcoma: therapy
KW  - Rhabdomyosarcoma: immunology
KW  - Rhabdomyosarcoma: radiotherapy
KW  - Rhabdomyosarcoma: pathology
KW  - Killer Cells, Natural: immunology
KW  - Killer Cells, Natural: metabolism
KW  - Killer Cells, Natural: transplantation
KW  - Mice
KW  - Receptors, Chimeric Antigen: metabolism
KW  - Immunotherapy, Adoptive: methods
KW  - Xenograft Model Antitumor Assays
KW  - Cell Line, Tumor
KW  - ErbB Receptors: metabolism
KW  - Female
KW  - Chimeric antigen receptor - CAR (Other)
KW  - Immunotherapy (Other)
KW  - Natural killer - NK (Other)
KW  - Radiotherapy/radioimmunotherapy (Other)
KW  - Solid tumor (Other)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
KW  - ErbB Receptors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40623716
C2  - pmc:PMC12232460
DO  - DOI:10.1136/jitc-2024-011330
UR  - https://inrepo02.dkfz.de/record/302815
ER  -