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- Title
Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment.
- Authors
Chikileva, Irina O.; Bruter, Alexandra V.; Persiyantseva, Nadezhda A.; Zamkova, Maria A.; Vlasenko, Raimonda Ya.; Dolzhikova, Yuliya I.; Shubina, Irina Zh.; Donenko, Fedor V.; Lebedinskaya, Olga V.; Sokolova, Darina V.; Pokrovsky, Vadim S.; Fedorova, Polina O.; Ustyuzhanina, Nadezhda E.; Anisimova, Natalia Yu.; Nifantiev, Nikolay E.; Kiselevskiy, Mikhail V.
- Abstract
Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 expression in a wide range of normal tissues. Thus, side effects are caused by CAR lymphocyte "on-target off-tumor" reactions. We aimed to develop safer HER2-targeting CAR-based therapy. CAR constructs against HER2 tumor-associated antigen (TAA) for transient expression were delivered into target T and natural killer (NK) cells by an effective and safe non-viral transfection method via nucleofection, excluding the risk of mutations associated with viral transduction. Different in vitro end-point and real-time assays of the CAR lymphocyte antitumor cytotoxicity and in vivo human HER2-positive tumor xenograft mice model proved potent cytotoxic activity of the generated CAR-T-NK cells. Our data suggest transient expression of anti-HER2 CARs in plasmid vectors by human lymphocytes as a safer treatment for HER2-positive human cancers. We also conducted preliminary investigations to elucidate if fucosylated chondroitin sulfate may be used as a possible agent to decrease excessive cytokine production without negative impact on the CAR lymphocyte antitumor effect.
- Subjects
XENOGRAFTS; CHONDROITIN sulfates; KILLER cells; CELL populations; EPIDERMAL growth factor receptors; CHIMERIC antigen receptors
- Publication
Biomedicines, 2023, Vol 11, Issue 9, p2563
- ISSN
2227-9059
- Publication type
Article
- DOI
10.3390/biomedicines11092563