EXTH-55. ANTI-TUMOR ACTIVITY OF A NEW ONCOLYTIC ADENOVIRUS DELTA-24-RGDOX-IL15 CO-EXPRESSING OX40L AND IL-15

Accumulating evidence show that the interaction between oncolytic viruses (OVs) and host immune system plays an essential role in cancer virotherapy. Compared to lytic potency of OVs, enhancement of OV-mediated anti-tumor immunity has become a more attractive strategy to improve OV efficacy. To this end, we have reported that the third-generation oncolytic adenovirus (OA), Delta-24-RGDOX, which expresses the immune co-stimulator OX40 ligand (OX40L), is more potent to elicit anti-tumor immunity than the second-generation OA Delta-24-RGD. Since IL-15 activates T and NK cells and promotes persistence of CD8⁺ memory T cells, we hypothesize that co-expression of OX40L and IL-15 by OAs will further potentiate their efficacy. For this purpose, we constructed the next generation OA Delta-24-RGDOX-IL15. In cultured human and murine tumor cell lines, this new virus effectively expressed the two molecules and displayed comparable potency in viral replication and oncolysis as OAs expressing either of the two (Delta-24-RGDOX, Delta-24-RGD-IL15). Then, we tested the anti-tumor activity of Delta-24-RGDOX-IL15 (two doses, intratumorally, one week interval) in two syngeneic tumor models in C57BL/6 mice: 1) intracranial (i.c.) gliomas from GL261-5 cells; 2) subcutaneous (s.c.)/i.c. melanomas from B16 cells (virus injected into s.c. tumors only). We found Delta-24-RGDOX-IL15 was more efficacious than the other two OAs to inhibit tumor growth of both treated tumor and the untreated i.c. tumors in the second model, leading to long-term survivors (p < 0.05). Different from adoptive cell therapies with cells engineered to express IL-15, we haven’t observed any obvious toxicity with this new virus when it was injected intratumorally into either the i.c. or s.c. tumors. Further studies are in progress to analyze the modifications of the tumor microenvironment induced by the addition of IL-15 to Delta-24-RGDOX. We expect this virus to be a good candidate to be combined with CAR T cell therapies.