Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteers DOI Creative Commons
Christian J. Maine, Shigeki J. Miyake-Stoner, Darina Spasova

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 7, 2025

Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions demonstrate immunogenicity safety preclinical clinical development. Optimized vaccines generate protective immunity (according WHO defined thresholds) at doses up 1,000,000-fold lower than female mouse models of influenza rabies. Clinically, RBI-4000, vector encoding rabies glycoprotein, was evaluated a Phase I study (NCT06048770). RBI-4000 able elicit de novo majority healthy participants when administered dose 0.1, 1, or 10 microgram (71%, 94%, 100%, respectively) prime-boost schedule. Similarly, observe above benchmark protection following single administration most both 1 doses. There serious reported across all cohorts. These data establish high therapeutic index vectors, demonstrating feasibility low approaches for applications. Here authors report self-replicating approach that generates much mice. In using glycoprotein as antigen, they show robust responses 0.1 µg, favorable

Language: Английский

Neoantigens: promising targets for cancer therapy DOI Creative Commons
Na Xie, Guobo Shen, Wei Gao

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 6, 2023

Abstract Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by cells as a result various tumor-specific alterations, such genomic mutation, dysregulated RNA splicing, disordered post-translational modification, integrated viral open reading frames. recognized non-self trigger an immune response that is not subject to central peripheral tolerance. The quick identification prediction neoantigens been made possible advanced next-generation sequencing bioinformatic technologies. Compared tumor-associated antigens, highly immunogenic provide emerging targets personalized serve prospective predictors survival prognosis checkpoint blockade responses. therapies will be aided understanding mechanism underlying neoantigen-induced anti-tumor streamlining process neoantigen-based immunotherapies. This review provides overview on characterization outlines clinical applications immunotherapeutic strategies based neoantigens. We also explore their current status, inherent challenges, translation potential.

Language: Английский

Citations

483
Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study DOI
Jeffrey S. Weber, Matteo S. Carlino,

Adnan Khattak

et al.

The Lancet, Journal Year: 2024, Volume and Issue: 403(10427), P. 632 - 644

Published: Jan. 21, 2024

Language: Английский

Citations

278
mRNA-based cancer therapeutics DOI
Chuang LIU,

Qiangqiang Shi,

Xiangang Huang

et al.

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(8), P. 526 - 543

Published: June 13, 2023

Language: Английский

Citations

227
Therapeutic cancer vaccines: advancements, challenges and prospects DOI Creative Commons
Ting Fan, Mingna Zhang, Jingxian Yang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 13, 2023

With the development and regulatory approval of immune checkpoint inhibitors adoptive cell therapies, cancer immunotherapy has undergone a profound transformation over past decades. Recently, therapeutic vaccines have shown promise by eliciting de novo T responses targeting tumor antigens, including tumor-associated antigens tumor-specific antigens. The objective was to amplify diversify intrinsic repertoire cells. However, complete realization these capabilities remains an ongoing pursuit. Therefore, we provide overview current landscape in this review. range antigen selection, delivery systems strategic nuances underlying effective presentation pioneered vaccine design. Furthermore, review addresses status clinical trials discusses their strategies, focusing on immunogenicity anti-tumor efficacy assessment. attempts toward developing not yielded breakthrough outcomes due significant challenges, microenvironment suppression, optimal candidate identification, response evaluation, manufacturing acceleration. field is poised overcome hurdles improve patient future acknowledging complexities persistently striving surmount inherent constraints.

Language: Английский

Citations

221
Precision treatment in advanced hepatocellular carcinoma DOI Creative Commons
Xupeng Yang, Chen Yang, Shu Zhang

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(2), P. 180 - 197

Published: Feb. 1, 2024

The past decade has witnessed significant advances in the systemic treatment of advanced hepatocellular carcinoma (HCC). Nevertheless, newly developed strategies have not achieved universal success and HCC patients frequently exhibit therapeutic resistance to these therapies. Precision represents a paradigm shift cancer recent years. This approach utilizes unique molecular characteristics individual patient personalize modalities, aiming maximize efficacy while minimizing side effects. Although precision shown multiple types, its application remains infancy. In this review, we discuss key aspects HCC, including biomarkers, classifications, heterogeneity tumor microenvironment. We also propose future directions, ranging from revolutionizing current methodologies personalizing therapy through functional assays, which will accelerate next phase advancements area.

Language: Английский

Citations

139
Antigen presentation in cancer — mechanisms and clinical implications for immunotherapy DOI
Kailin Yang, Ahmed Halima, Timothy A. Chan

et al.

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(9), P. 604 - 623

Published: June 16, 2023

Language: Английский

Citations

124
Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial DOI Creative Commons
Shubham Pant, Zev A. Wainberg, Colin D. Weekes

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(2), P. 531 - 542

Published: Jan. 9, 2024

Pancreatic and colorectal cancers are often KRAS mutated incurable when tumor DNA or protein persists recurs after curative intent therapy. Cancer vaccine ELI-002 2P enhances lymph node delivery immune response using amphiphile (Amph) modification of G12D G12R mutant (mKRAS) peptides (Amph-Peptides-2P) together with CpG oligonucleotide adjuvant (Amph-CpG-7909). We treated 25 patients (20 pancreatic five colorectal) who were positive for minimal residual mKRAS disease (ctDNA and/or serum antigen) locoregional treatment in a phase 1 study fixed-dose Amph-Peptides-2P ascending-dose Amph-CpG-7909; enrollment is complete patient follow-up ongoing. Primary endpoints included safety recommended 2 dose (RP2D). The secondary endpoint was biomarker (longitudinal ctDNA antigen), exploratory including immunogenicity relapse-free survival (RFS). No dose-limiting toxicities observed, the RP2D 10.0 mg Amph-CpG-7909. Direct ex vivo mKRAS-specific T cell responses observed 21 (84%; 59% both CD4

Language: Английский

Citations

92
Clinical delivery of circular RNA: Lessons learned from RNA drug development DOI
Tiana L. Young, Kevin Chang Wang, Andrew Varley

et al.

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 197, P. 114826 - 114826

Published: April 23, 2023

Language: Английский

Citations

72
Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial DOI Creative Commons
Mark Yarchoan, Edward Gane, Thomas U. Marron

et al.

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

Citations

71
Recent advances in mRNA cancer vaccines: meeting challenges and embracing opportunities DOI Creative Commons
Bolin Wang,

Jinli Pei,

Shengnan Xu

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 6, 2023

Since the successful application of messenger RNA (mRNA) vaccines in preventing COVID-19, researchers have been striving to develop mRNA for clinical use, including those exploited anti-tumor therapy. cancer emerged as a promising novel approach immunotherapy, offering high specificity, better efficacy, and fewer side effects compared traditional treatments. Multiple therapeutic are being evaluated preclinical trials, with early-phase results. However, development these faces various challenges, such tumor heterogeneity, an immunosuppressive microenvironment, practical obstacles like vaccine administration methods evaluation systems application. To address we highlight recent advances from studies trials that provide insight into identifying associated discuss potential strategies overcome them. In future, it is crucial caution diligence while promoting innovation existing barriers. A delicate balance between opportunities challenges will help guide progress this field towards its full potential.

Language: Английский

Citations

66