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

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 Full article

Journal

Biomedicines
ISSN: 2227-9059

Output data

Year: 2023, Volume: 11, Number: 9, Article number : 2563, Pages count : DOI: 10.3390/biomedicines11092563

Authors

Chikileva Irina O. ¹ , Bruter Alexandra V. ² , Persiyantseva Nadezhda A. ³ , Zamkova Maria A. ³ , Vlasenko Raimonda Ya. ¹ , Dolzhikova Yuliya I. ¹ , Shubina Irina Zh. ¹ , Donenko Fedor V. ¹ , Lebedinskaya Olga V. ⁴ , Sokolova Darina V. ^5,1 , Pokrovsky Vadim S. ^5,1 , Fedorova Polina O. ^6,7,1 , Ustyuzhanina Nadezhda E. ⁸ , Anisimova Natalia Yu. ¹ , Nifantiev Nikolay E. ⁸ , Kiselevskiy Mikhail V. ¹

Affiliations

1	Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia
2	Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia
3	Research Institute of Carcinogenesis, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia
4	Department of Histology, Embryology and Cytology, EA Vagner Perm State Medical University, 614000 Perm, Russia
5	Patrice Lumumba Peoples’ Friendship University, 117198 Moscow, Russia
6	II Mechnikov Research Institute of Vaccines and Serums, 105064 Moscow, Russia
7	Microbiology, Virology and Immunology Department, Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119991 Moscow, Russia
8	ND Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia

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.

Chikileva I.O. , Bruter A.V. , Persiyantseva N.A. , Zamkova M.A. , Vlasenko R.Y. , Dolzhikova Y.I. , Shubina I.Z. , Donenko F.V. , Lebedinskaya O.V. , Sokolova D.V. , Pokrovsky V.S. , Fedorova P.O. , Ustyuzhanina N.E. , Anisimova N.Y. , Nifantiev N.E. , Kiselevskiy M.V.
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
Biomedicines. 2023. V.11. N9. 2563 . DOI: 10.3390/biomedicines11092563 WOS Scopus OpenAlex

≡ Web of science:	WOS:001074518900001
≡ Scopus:	2-s2.0-85172444857
≡ OpenAlex:	W4386874460