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.

Autor: Chikileva IO; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Bruter AV; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, 119334 Moscow, Russia., Persiyantseva NA; Research Institute of Carcinogenesis, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Zamkova MA; Research Institute of Carcinogenesis, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Vlasenko RY; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Dolzhikova YI; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Shubina IZ; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Donenko FV; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Lebedinskaya OV; Department of Histology, Embryology and Cytology, EA Vagner Perm State Medical University, 614000 Perm, Russia., Sokolova DV; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia.; Patrice Lumumba Peoples' Friendship University, 117198 Moscow, Russia., Pokrovsky VS; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia.; Patrice Lumumba Peoples' Friendship University, 117198 Moscow, Russia., Fedorova PO; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia.; 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.; II Mechnikov Research Institute of Vaccines and Serums, 105064 Moscow, Russia., Ustyuzhanina NE; ND Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia., Anisimova NY; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia., Nifantiev NE; ND Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russia., Kiselevskiy MV; Research Institute of Experimental Therapy and Diagnostics of Tumor, NN Blokhin National Medical Center of Oncology, 115478 Moscow, Russia.
Jazyk: angličtina
Zdroj: Biomedicines [Biomedicines] 2023 Sep 18; Vol. 11 (9). Date of Electronic Publication: 2023 Sep 18.
DOI: 10.3390/biomedicines11092563
Abstrakt: 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.
Databáze: MEDLINE