mRNA to modulate immune cells within tumors

Delivery of messenger RNA (mRNA) encoding interferon regulatory factor 8 (IRF8) or NF-κB-inducing kinase (NIK) in lipid nanoparticles (LNPs) produced sustained antitumor responses across several mouse tumor models. The study, published in Nature Biotechnology, evaluated a strategy for modulating immune cells in the tumor microenvironment. In a separate vaccine experiment that included antigen mRNA, the researchers also reported increased antigen-specific immune responses and prevention of tumor growth.

Cancer immunotherapy works for some patients, but an immunosuppressive tumor microenvironment remains an obstacle to extending its benefits. The researchers focused on environments lacking functional tumor-specific T cells, antigen-presenting cells (APCs), and tumor-infiltrating lymphocytes. Their approach examined both the number and function of cells that could drive an immune response within tumors.

The researchers packaged immune-modulating mRNA designed to express IRF8 or NIK in LNPs and delivered it to immune cells in the tumor microenvironment. The central strategy was to modulate immune-cell function by expressing these factors. The available abstract describes NIK or IRF8; it cannot be interpreted as evidence of a synergistic effect when the two factors are administered together.

APC activation and effects of vaccine co-administration

The immune-modulating mRNA activated APCs within tumors. Activated type 1 conventional dendritic cells (cDC1s) and immunostimulatory cytokines increased, and an initial antitumor CD8+ T-cell response was induced. These findings report both activation of cells that present antigens within tumors and an antitumor T-cell response.

LNP-encapsulated mRNA induced sustained antitumor responses in several syngeneic mouse tumor models. The responses were observed with both intratumoral and intravenous administration. However, the abstract does not specify the cancer types, number of administrations or doses, magnitude of tumor suppression, or observation period, making it difficult to compare the effects of the delivery routes quantitatively.

A vaccine experiment co-administering antigen mRNA assessed immune responses and tumor prevention. When ovalbumin mRNA was combined with the immune-modulating mRNA, the antigen-specific CD8+ T-cell response increased approximately tenfold. The researchers reported that long-term immune memory was maintained and that tumor growth was prevented in vaccinated mice.

The approximately tenfold figure refers to the increase in the antigen-specific T-cell response. It does not mean that the antitumor treatment effect was ten times greater. The abstract does not describe the comparison groups in detail or state how long immune memory was observed. Nor should this vaccine experiment be described as showing rejection of a cancer-cell rechallenge after prior tumor treatment.

Potential for cancer treatment and vaccine-adjuvant strategies

This study presents an mRNA strategy for modulating immune cells in the tumor microenvironment and an adjuvant strategy for enhancing responses to antigen mRNA vaccines. Sustained antitumor responses in the tumor-treatment experiments and immune memory and tumor prevention in the vaccine experiments were achieved under different conditions. Follow-up studies should keep the treatment and prevention objectives distinct.

Before applying the approach in humans, efficacy and safety by delivery route and appropriate dosing conditions will need further evaluation. The materials available for this review were limited to the paper’s bibliographic information and abstract, making it difficult to assess differences among models, adverse effects, or the specific duration of responses. Mouse results alone cannot establish that the approach overcomes resistance to existing immunotherapies or demonstrate treatment benefit in patients.

The study details and numerical results can be found in the paper’s bibliographic record and abstract indexed in Europe PMC.