Efficient Colorectal Cancer Gene Therapy with IL-15 mRNA Nanoformulation

Abstract

Immunogene therapy is a novel method for the treatment of colorectal cancer. Cytokine IL-15 has exhibited therapeutic anticancer potential due to its immune-stimulation property. However, conventional IL-15-based cancer gene therapy studies have been performed using the plasmid DNA form, which has potential shortcomings including weak delivery efficiency and backbone effect. In this study, an IL-15 immunogene therapy study for colon cancer using in vitro transcript mRNA is described. A protamine/liposome system (CLPP) is developed to provide efficient condensation and delivery capacity for in vivo mRNA transportation. They demonstrated that the prepared CLPP system could deliver the IL-15-encoding mRNA into C26 cells with high efficacy. The secretory expressed IL-15 cytokine by the C26 cells successfully produced lymphocyte stimulation and triggered anticancer cytotoxicity upon cancer cells in vitro. Local or systemic administration of the CLPP/mIL-15 complex exhibited obvious inhibition effects on multiple C26 murine colon cancer models with inhibition rates of up to 70% in the C26 abdominal cavity metastasis tumor model, 55% in the subcutaneous model, and 69% in the pulmonary metastasis model, demonstrating high efficacy and safety. These results successfully demonstrated the high therapeutic potential of the CLPP/mIL-15 complex for colorectal cancer immunogene therapy.

Lipid nanoparticles for mRNA delivery

“…Alternatively to vaccination, a pro-inflammatory tumour microenvironment can be induced by lipid nanoparticle–mRNA formulations delivering cytokines or co-stimulatory molecules 33 , 106 , 161 , 163 , 214 (Table 2 ). For example, mRNA-2416, a lipid nanoparticle encapsulating mRNA encoding human OX40L (a ligand of OX40), is in clinical evaluation for the treatment of patients with solid tumours (NCT03323398) 214 .…”

Functionalized DMP-039 Hybrid Nanoparticle as a Novel mRNA Vector for Efficient Cancer Suicide Gene Therapy

“… 49 Lei et al synthesized a protamine/cationic liposome system to deliver IL15 mRNA, and this complex was able to treat colon cancer in a lung metastatic tumor model by systemic administration. 50 Pardi et al reported that LNP-supported delivery of modified mRNA resulted in high translation rates for a short time by intravenous administration. 51 …”

mRNA, a Revolution in Biomedicine

“…Local or systemic administration of this mRNA induced inhibition of cellular proliferation in several colon cancer models in a safe and efficient way. These results have shown the high therapeutic potential for colorectal cancer immunogenic therapy with this approach [83]. In the same context, Interleukin 2 (IL-2) exerts significant anti-tumor activity.…”