RNA aggregates harness the danger response for potent cancer immunotherapy

Area of Science:

• Immunology
• Oncology
• Nanotechnology
• RNA Therapeutics

Background:

• Cancer immunotherapy faces challenges due to poor antigenicity and immunosuppressive tumor microenvironments (TME).
• Current mRNA vaccines often rely on nanoparticle cores for immune cell receptor engagement, limiting broader TME reprogramming.

Purpose of the Study:

• To develop novel RNA lipid particle aggregates (LPAs) for enhanced cancer immunotherapy.
• To investigate the mechanism of action and therapeutic efficacy of RNA-LPAs in preclinical and clinical settings.

Main Methods:

• Creation of "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) for improved mRNA antigen packaging and immunogenicity.
• Systemic administration of RNA-LPAs to activate RIG-I in stromal cells, inducing cytokine/chemokine responses and immune cell trafficking.
• Evaluation of RNA-LPAs in murine tumor models, client-owned canines with gliomas, and a first-in-human glioblastoma trial.

Main Results:

• RNA-LPAs activated stromal cells via RIG-I, leading to massive cytokine/chemokine release and immune cell infiltration.
• Significant tumor rejection was observed in both early- and late-stage murine tumor models.
• In canines and glioblastoma patients, RNA-LPAs improved survivorship, reprogrammed the TME to a "hot" state, and induced glioma-specific immune responses.

Conclusions:

• RNA-LPAs represent a novel technology that simultaneously reprograms the tumor microenvironment and elicits potent anti-cancer immunity.
• This approach demonstrates rapid and enduring therapeutic effects, offering a promising new strategy for cancer immunotherapy.