Enhanced anti-tumor activity by Zinc Finger Repressor-driven epigenetic silencing of immune checkpoints and TGFBR2 in CAR-T cells and TILs DOI Open Access
Marion David, Phillip Schiele, Davide Monteferrario

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 12, 2024

ABSTRACT CAR-T therapies have shown remarkable success in treating hematological malignancies. However, effectiveness against solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), such as TGF-β signaling and upregulated immune checkpoints (ICs). Furthermore, identifying universal, tumor-specific targets for cells is challenging, but using reinvigorated, immunosuppressive-resistant tumor-infiltrating lymphocytes (TILs) could be a promising alternative approach. Unlike nucleases, which may induce genotoxic DNA double-strand breaks, multiplexed Zinc Finger Repressors (ZFR) offer safer knocking out TME-related factors. We epigenetically repressed PD-1 expression both TILs from colorectal liver metastases. repression did not affect T cell viability, proliferation, or functionality. In murine B lymphoma model, PD-1-repressed CD19-CAR-T exhibited enhanced anti-tumor activity improved survival. Notably, alone increase cytotoxicity PD-L1-positive line vitro. To further potency this context, ZFR-expressing lentiviral vectors targeting other ICs (LAG-3, TIM-3, TIGIT) TGFBR2 were developed, improving significantly cytotoxic TILs. This strategy highlights potential enhance tumor-reactive improve anti-cancer immunotherapies by repressing factors TME ZFRs.

Language: Английский

Synthetic Gene Circuits as a Promising Approach in Cancer Immunotherapy DOI
Bhanuprakash Ananthakumar,

Nagashri Nanjundeshwara,

Archana Lakshmaiah

et al.

Advances in medical diagnosis, treatment, and care (AMDTC) book series, Journal Year: 2024, Volume and Issue: unknown, P. 391 - 418

Published: Aug. 28, 2024

Cancer immunotherapy has emerged as a revolutionary approach in the fight against cancer. Unlike traditional treatments like chemotherapy and radiation, harnesses power of body's own immune system to identify destroy cancer cells. promising therapy, but limitations specificity control hinder its full potential. Synthetic gene circuits offer address these challenges. This chapter emphasizes diverse applications synthetic immunotherapy. Additionally, authors discuss advantages AND gate for minimizing off-target effects, engineered bacteria targeted tumour manipulation, T-cell engineering enhanced anti-tumour activity. Ultimately, therapies are not mutually exclusive. While proven effectiveness accessibility, hold immense promise personalized, long-term solutions.

Language: Английский

Citations

5
Acetylshikonin induces cell necroptosis via mediating mitochondrial function and oxidative stress-regulated signaling in human Oral Cancer cells DOI
Kun Shao, Sheng‐Dean Luo, Eng‐Yen Huang

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108396 - 108396

Published: March 1, 2025

Language: Английский

Citations

0
Pyruvate kinase M2 activation reprograms mitochondria in CD8 T cells, enhancing effector functions and efficacy of anti-PD1 therapy DOI
Seyedeh Sahar Mortazavi Farsani, Jigar Y. Soni, Lu Jin

et al.

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
The physiological and pathological roles of RNA modifications in T cells DOI

Yu Deng,

Jing Zhou, Huabing Li

et al.

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(9), P. 1578 - 1592

Published: July 9, 2024

Language: Английский

Citations

1
Enhanced anti-tumor activity by Zinc Finger Repressor-driven epigenetic silencing of immune checkpoints and TGFBR2 in CAR-T cells and TILs DOI Open Access
Marion David, Phillip Schiele, Davide Monteferrario

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 12, 2024

ABSTRACT CAR-T therapies have shown remarkable success in treating hematological malignancies. However, effectiveness against solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), such as TGF-β signaling and upregulated immune checkpoints (ICs). Furthermore, identifying universal, tumor-specific targets for cells is challenging, but using reinvigorated, immunosuppressive-resistant tumor-infiltrating lymphocytes (TILs) could be a promising alternative approach. Unlike nucleases, which may induce genotoxic DNA double-strand breaks, multiplexed Zinc Finger Repressors (ZFR) offer safer knocking out TME-related factors. We epigenetically repressed PD-1 expression both TILs from colorectal liver metastases. repression did not affect T cell viability, proliferation, or functionality. In murine B lymphoma model, PD-1-repressed CD19-CAR-T exhibited enhanced anti-tumor activity improved survival. Notably, alone increase cytotoxicity PD-L1-positive line vitro. To further potency this context, ZFR-expressing lentiviral vectors targeting other ICs (LAG-3, TIM-3, TIGIT) TGFBR2 were developed, improving significantly cytotoxic TILs. This strategy highlights potential enhance tumor-reactive improve anti-cancer immunotherapies by repressing factors TME ZFRs.

Language: Английский

Citations

0