Human IL12A mRNA

Retroviral gene transfer of interleukin-12 (IL-12) to T cells significantly enhances antitumor efficacy after adoptive transfer, but has shown unacceptable severe side effects in the clinic. To overcome toxicity, researchers have engineered tumor-specific CD8+ T cells to transiently express IL-12. Injection of genetically engineered T cells into tumors (rather than intravenously) leads to complete rejection not only of the injection site but also of distant concomitant tumors. Co-injection with agonist anti-CD137 mAbs or transient co-expression of CD137 ligands further enhances efficacy. The therapy induces epitope spreading of endogenous CD8+ T cell immune responses in a cDC1 dendritic cell-dependent manner. Mouse and human tumor-infiltrating T lymphocyte cultures can achieve significant immunotherapeutic effects by transient IL-12 genetic engineering.

Here, researchers show that human single-chain IL-12 (scIL-12) mRNA (Figure 1A) can be electroporated into patient lymphocyte cultures to induce intracellular expression of human IL-12p40 and high levels of IFN-γ (Figures 1B-1E). In addition, they explored this approach in a patient with endometrial cancer whose TILs had been isolated and expanded, and whose tumors could be transplanted into immunodeficient mice and serially passaged as patient-derived xenografts (PDXs). These TILs could be functionally electroporated with IL-12 mRNA (Figure 1E) and used to treat PDXs intratumorally (Figure 1F). Under these conditions, IL-12 mRNA electroporation combined with low-dose (5 μg each) anti-CD137 mAb urelumab co-injection controlled tumor progression (Figure 1G). In contrast, intratumoral injection of mock-electroporated TILs produced only a weak therapeutic effect (Figure 1G).

Figure 1. Transient IL-12 Expression and IFN-γ Production following Human scIL-12 mRNA Electroporation into Human TILs to Enhance Their Antitumor Activity. (Etxeberria I, et al., 2019)