- [INMUNOMODULACIÓN Y MICROAMBIENTE TUMORAL]
- [TERAPIA GÉNICA Y REGULACIÓN DE LA EXPRESIÓN GÉNICA]
- [INMUNOLOGÍA E INMUNOTERAPIA]
Intratumoral electroporation of a self-amplifying RNA expressing IL-12 induces antitumor effects in mouse models of cancer
Noelia Silva-Pilipich 1 2, Aritz Lasarte-Cía 3 2, Teresa Lozano 3 2, Celia Martín-Otal 3 2, Juan José Lasarte 3 2, Cristian Smerdou 1 2
Alphavirus vectors based on self-amplifying RNA (saRNA) generate high and transient levels of transgene expression and induce innate immune responses, making them an exciting tool for antitumor therapy. These vectors are usually delivered as viral particles, but it is also possible to administer them as RNA.
We evaluated this possibility by in vivo electroporation of Semliki Forest virus (SFV) saRNA for local treatment of murine colorectal MC38 subcutaneous tumors. Optimization of saRNA electroporation conditions in tumors was performed using an SFV vector coding for luciferase. Then, we evaluated the therapeutic potential of this approach using an SFV saRNA coding for interleukin-12 (SFV-IL-12), a proinflammatory cytokine with potent antitumor effects. Delivery of SFV-IL-12 saRNA by electroporation improved tumor control and higher survival compared with mice treated with electroporation or with SFV-IL-12 saRNA alone.
The antitumor efficacy of SFV-IL-12 saRNA electroporation increased in combination with systemic PD-1 blockade. This therapy, also validated in a hepatocellular carcinoma tumor model, suggests that local delivery of saRNA by electroporation could be an attractive strategy for cancer immunotherapy. This approach could easily be translated into clinical practice, especially for percutaneously accessible tumors.
Keywords: MT: Delivery Strategies; Semliki Forest virus; cancer gene therapy; immunotherapy, colorectal cancer, melanoma; interleukin-12; in vivo electroporation; self-amplifying RNA.