67P - The effect of non-viral gene-immune therapy via OX40L or 4-1BBL on murine subcutaneous CT26 colon cancer model

Background

One way to significantly reduce the incidence of systemic side effects of antitumoral immunotherapeutics is intratumoral gene-immune therapy. The use of non-viral systems is attractive for gene therapy due to low immunogenicity of the carrier, low production costs, and relatively high capacity. Thus, non-viral intratumoral gene-immune therapy is a promising area for development of antitumor drugs. OX40 and 4-1BB T cell co-stimulators are popular targets in immunotherapeutic drug development, but currently there are no approved drugs targeting these receptors. We suppose that the natural ligands of these receptors, OX40L and 4-1BBL, would be effective in non-viral gene-immune therapeutics.

Methods

The antitumor effect of stable OX40L or 4-1BBL expression by inoculated cancer cells on CT26 tumor growth was studied. CT26 cell lines stably expressing OX40L or 4-1BBL were obtained, tumor graftability and growth in BALB/c mice were evaluated. Next, antitumor effect of non-viral gene-immune therapy with OX40L or 4-1BBL was studied, complexes of polymeric carrier with plasmid DNA encoding OX40L or 4-1BBL were prepared and injected three times into CT26wt subcutaneous tumors in BALB/c mice, starting when tumors reached 50±15 mm³ .

Results

Stable expression of OX40L and 4-1BBL significantly suppressed CT26 tumor growth, delayed tumor resorption was observed in the experimental groups. The use of OX40L and 4-1BBL in the context of gene-immune therapy had a significant effect on CT26 tumor growth – median animal survival compared to the control group was increased by 26.5% (OX40L) and 41.2% (4-1BBL), life expectancy was increased by 24% (OX40L) and 24.5% (4-1BBL), tumor growth inhibition 10 days after treatment was 70% (OX40L) and 71.3% (4-1BBL). No visible immune-related adverse events (irAEs) were observed.

Conclusions

OX40L and 4-1BBL have a comparable potent antitumoral effect on CT26 tumor growth in the context of non-viral gene-immune therapy, and such therapeutic approach does not yield visible systemic irAEs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Group of Gene Immuno Oncotherapy, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry.

Funding

This study was supported by RSF grant 22-25-00806, https://rscf.ru/project/22-25-00806/.

Disclosure

All authors have declared no conflicts of interest.