NKG2D/CD28 chimeric receptor boosts cytotoxicity and durability of CAR-T cells for solid and hematological tumors DOI Creative Commons

Xia Teng,

Shance Li,

Chaoting Zhang

et al.

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: April 3, 2025

Abstract Background CAR-T cell therapy faces challenges in solid tumor treatment and hematologic malignancy relapse, among which the limited persistence of cells target antigen downregulation are prominent factors. Therefore, we engineered an NKG2D/CD28 chimeric co-stimulatory receptor (CCR), leveraging its broad ligand expression on tumors to enhance antitumor activity MSLN CAR CD19 cells. Methods We generated co-expressing CCR assessed their efficacy vitro vivo. activation, differentiation, exhaustion were analyzed over time following stimulation. Furthermore, a chronic stimulation model was established using with low density simulate sustained antigenic pressure encountered vivo conditions. Results Our study shows that NKG2D/CD28&CAR-T exhibit enhanced cytotoxicity against cells, especially those density, both Compared conventional second-generation or these dual-targeted demonstrate superior sensitivity recognizing lysing low-density antigen-expressing lung cancer leukemia they capable eradicating complementary co-stimulation provided by 4-1BB CD28 intracellular domains promotes cytokine secretion, reduces exhaustion, enhances significantly improving efficacy. Conclusion The combination offers potent strategy durability This approach is promising for therapeutic outcomes hematological preventing recurrence density.

Language: Английский

Enhancing CAR T-Cell Function with Domains of Innate Immunity Sensors DOI Open Access

Tjaša Mlakar,

Mojca Skrbinek,

Tina Fink

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1339 - 1339

Published: Feb. 5, 2025

The innate immune system plays an important role in protecting the organism via recognizing danger signals and pathogens through pattern recognition receptors. By sensing signal conveying signaling towards elimination of threat, several families these receptors, expressed on different myeloid lymphoid cells, serve as first defense line immunity. Toll-like C-type lectin many other receptors therefore illustrate importance protective system. This was additionally confirmed by CAR T-cell-based cancer immunotherapy, where patient’s own is being used for successful tumor elimination. T-cells have proven themselves to be a potent therapeutic option, yet some cases their efficiency could enhanced. Innate sensors that include strong activation domains, instance, part MyD88 (Myeloid Differentiation Primary Response gene), NKG2D (Natural killer group 2-member D), building module increase functionality potency T-cells.

Language: Английский

Citations

0
NKG2D/CD28 chimeric receptor boosts cytotoxicity and durability of CAR-T cells for solid and hematological tumors DOI Creative Commons

Xia Teng,

Shance Li,

Chaoting Zhang

et al.

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: April 3, 2025

Abstract Background CAR-T cell therapy faces challenges in solid tumor treatment and hematologic malignancy relapse, among which the limited persistence of cells target antigen downregulation are prominent factors. Therefore, we engineered an NKG2D/CD28 chimeric co-stimulatory receptor (CCR), leveraging its broad ligand expression on tumors to enhance antitumor activity MSLN CAR CD19 cells. Methods We generated co-expressing CCR assessed their efficacy vitro vivo. activation, differentiation, exhaustion were analyzed over time following stimulation. Furthermore, a chronic stimulation model was established using with low density simulate sustained antigenic pressure encountered vivo conditions. Results Our study shows that NKG2D/CD28&CAR-T exhibit enhanced cytotoxicity against cells, especially those density, both Compared conventional second-generation or these dual-targeted demonstrate superior sensitivity recognizing lysing low-density antigen-expressing lung cancer leukemia they capable eradicating complementary co-stimulation provided by 4-1BB CD28 intracellular domains promotes cytokine secretion, reduces exhaustion, enhances significantly improving efficacy. Conclusion The combination offers potent strategy durability This approach is promising for therapeutic outcomes hematological preventing recurrence density.

Language: Английский

Citations

0