Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1044 - 1053

Published: April 1, 2024

Abstract Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 through the induction of tumor-specific immunity. We present results from single-arm, open-label, phase 1/2 study DNA plasmid PTCV (GNOS-PV02) encoding up 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab patients advanced HCC previously treated multityrosine kinase inhibitor. Safety and immunogenicity were assessed primary endpoints, treatment feasibility evaluated secondary endpoints. The most common treatment-related adverse events injection-site reactions, observed 15 36 (41.6%) patients. No dose-limiting toxicities or grade ≥3 observed. objective response rate (modified intention-to-treat) per Response Evaluation Criteria Solid Tumors 1.1 was 30.6% (11 patients), 8.3% (3 36) achieving complete response. Clinical associated number encoded vaccine. Neoantigen-specific T confirmed 19 22 (86.4%) evaluable by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative cytolytic vaccine-specific CD4 + CD8 effector cells. receptor β-chain (TCRβ) bulk sequencing demonstrated vaccination-enriched clone expansion tumor infiltration. Single-cell analysis posttreatment clonal cytotoxic phenotypes. TCR complementarity-determining region cloning expanded clones tumors following vaccination reactivity against vaccine-encoded neoantigens. Our support PTCV’s mechanism action based on antitumor cells show that has clinical activity HCC. ClinicalTrials.gov identifier: NCT04251117 .

Language: Английский

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Therapeutic resistance to anti-oestrogen therapy in breast cancer

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(10), P. 673 - 685

Published: July 27, 2023

Language: Английский

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Ultrathin Clay Nanoparticles‐Mediated Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy

Advanced Materials, Journal Year: 2023, Volume and Issue: 36(9)

Published: Nov. 8, 2023

Ferroptosis-triggered immunogenic cell death (ICD) is widely adopted to potentiate the body's antitumor immunity by catalyzing production of toxic reactive oxygen species (ROS). However, efficacy ferroptosis and immunotherapy greatly restricted intracellular abundant glutathione (GSH) immunosuppressive tumor microenvironment (TME). Herein, a facile bottom-up method for solvent-free synthesis ultrathin manganese (Mn)-based layered double hydroxide nanosheets with high loading efficiency pro-inflammatory cytokine interferon (IFNγ) (IFNγ/uMn-LDHs) proposed mutually reinforce systemic immunity. The introduction ions significantly contributes GSH depletion hydroxyl radical generation, which can be further enhanced IFNγ delivery-induced SLC7A11 downregulation. ICD effect after cooperates intrinsic immunomodulatory property IFNγ/uMn-LDHs facilitate maturation dendritic cells (DCs) priming T cells. secretion from activated CD8

Language: Английский

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RNA‐based medicine: from molecular mechanisms to therapy

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(21)

Published: Sept. 20, 2023

Abstract RNA‐based therapeutics have the potential to revolutionize treatment and prevention of human diseases. While early research faced setbacks, it established basis for breakthroughs in drug design that culminated extraordinarily fast development mRNA vaccines combat COVID‐19 pandemic. We now reached a pivotal moment where RNA medicines are poised make broad impact clinic. In this review, we present an overview different strategies generate novel therapeutics, including antisense RNAi‐based mechanisms, mRNA‐based approaches, CRISPR‐Cas‐mediated genome editing. Using three rare genetic diseases as examples, highlight opportunities, but also challenges wide‐ranging applications class drugs.

Language: Английский

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Strategies for non-viral vectors targeting organs beyond the liver

Nature Nanotechnology, Journal Year: 2023, Volume and Issue: 19(4), P. 428 - 447

Published: Dec. 27, 2023

Language: Английский

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