TY  - JOUR
AU  - Moser, Laura M
AU  - Heim, Catrin
AU  - Koschade, Sebastian E
AU  - Wendel, Philipp
AU  - Bozkurt, Süleyman
AU  - Harenkamp, Sabine
AU  - Kreyenberg, Hermann
AU  - Merker, Michael
AU  - Münch, Christian
AU  - Gradhand, Elise
AU  - Vogler, Meike
AU  - Ullrich, Evelyn
AU  - Bönig, Halvard
AU  - Klusmann, Jan-Henning
AU  - Bader, Peter
AU  - Wels, Winfried S
AU  - Rettinger, Eva
TI  - CAR-CIK vs. CAR-T: benchmarking novel cytokine-induced killer cells as solid tumor immunotherapy in ErbB2+ rhabdomyosarcoma.
JO  - Frontiers in immunology
VL  - 16
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2025-00382
SP  - 1485817
PY  - 2025
AB  - CAR-T cell therapy, though successful in hematologic malignancies, faces challenges in solid tumors due to limitations of autologous T cells. Cytokine-induced killer (CIK) cells can be given safely across allogeneic barriers and constitute alternative effector cells generated from healthy donors. CIK cells are a heterogenous population of predominantly T cells with a mixed natural killer (NK) phenotype and combine non-MHC-restricted cytotoxicity with potent anti-tumor capacity of the adaptive immune system. Here, we characterize and compare efficacy, phenotypic subpopulations and modes of action of CAR-CIK cells and conventional CAR-T cells from same-donor samples in ErbB2+ rhabdomyosarcoma (RMS).To benchmark CAR-CIK against conventional CAR-T cells, effector cells were generated from same-donor samples and lentivirally transduced with a second generation CD28-CD3ζ CAR. Effector subpopulations and their dynamics upon target cell exposure were phenotypically characterized by flow cytometry. Efficacy was assessed in human ErbB2+ RMS cancer cell lines and primary patient samples in vitro and ex vivo using cytotoxicity and spheroid co-incubation assays. Modes of action were assessed by comparing cytokine secretion profiles using bead-based multiplexed flow cytometry and by liquid chromatography mass spectrometry whole cell proteomics. Finally, we used an in vivo model of RMS mimicking minimal metastatic residual disease to compare anti-tumor potency of CAR-CIK vs. CAR-T cells and to assess their target organ infiltration.In vitro assays demonstrated superior cytotoxicity of CAR-CIK cells against RMS cell lines and primary tumor samples. Long-term co-incubation with tumor spheroids led to expansion of CAR-CIK cells and enrichment of CD3+CD56+ TNK cells. CAR-CIK cell cytokine signature showed significantly increased secretion of effector molecules like interferon-γ, perforin and granulysin, and lower secretion of Th2 cytokines IL-2, IL-4 and IL-10. Whole cell proteomics showed corresponding upregulation of chemokine signaling and NK-cytotoxicity pathways in CAR-CIK cells. In NSG mice xenografted with ErbB2+ RMS, a single injection of either CAR-effector cells strongly impeded metastatic tumor development and significantly improved survival.Our results demonstrate that CAR-CIK cells are at least equipotent to CAR-T cells. Combined with their favorable safety profile and allogeneic applicability, these findings position CAR-CIK cells as promising immune effectors for solid tumors.
KW  - Humans
KW  - Rhabdomyosarcoma: therapy
KW  - Rhabdomyosarcoma: immunology
KW  - Cytokine-Induced Killer Cells: immunology
KW  - Immunotherapy, Adoptive: methods
KW  - Animals
KW  - Receptor, ErbB-2: immunology
KW  - Receptors, Chimeric Antigen: immunology
KW  - Receptors, Chimeric Antigen: genetics
KW  - Receptors, Chimeric Antigen: metabolism
KW  - Mice
KW  - Cell Line, Tumor
KW  - Xenograft Model Antitumor Assays
KW  - Cytokines: metabolism
KW  - Cytotoxicity, Immunologic
KW  - Benchmarking
KW  - CAR-T (Other)
KW  - ERBB2 (Other)
KW  - cytokine-induced killer cells (CIK) (Other)
KW  - rhabdomyosarcoma (Other)
KW  - solid tumors (Other)
KW  - Receptor, ErbB-2 (NLM Chemicals)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
KW  - ERBB2 protein, human (NLM Chemicals)
KW  - Cytokines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39963129
C2  - pmc:PMC11831232
DO  - DOI:10.3389/fimmu.2025.1485817
UR  - https://inrepo02.dkfz.de/record/298948
ER  -