Combination therapy is a cornerstone of cancer treatment and has shown promising results in the clinical setting. Immunotherapies like oncolytic virotherapy, in addition to inducing cytolytic effects, can activate the immune response in patients, presenting a synergistic potential when combined with adoptive cellular therapies like CAR T cells.

Here, we introduce a new human oncolytic adenovirus, ISC301, which enhances the antitumor effect of CAR T cell therapy by inducing early activation of pro-inflammatory pathways after tumor infection. ISC301 is based in the oncolytic adenovirus ICOVIR-5, but incorporates the deletion of their natural penton RGD-motifs, maintaining the artificial RDG-motifs in the H1 loop of fibers.

In vitro, ISC301 induced similar antitumor effect than ICOVIR-5. However, in vivo antitumor efficacy of ISC301 was significantly higher than the observed with ICOVIR-5 only three days after systemic administration in an immunocompetent mouse model. In addition, increased early activation of pro-inflammatory pathways was observed in tumors treated with ISC301.

We then studied the combination of both oncolytic adenovirus with NKG2D-CAR T cell therapy in an immunodeficient tumor model. CAR T cells were administered one day after virus administration in order to take advantage of the induced pro-inflammatory response. Interestingly, the combination of NKG2D-CAR T cells with ISC301 showed significant higher antitumor effect in vitro and in vivo than in combination with ICOVIR-5.

In conclusion, the new oncolytic adenovirus ISC301 induces antitumor efficacy and enhances the antitumor effect of CAR T cell therapy. This improvement seems to be based on a higher activation of the tumor infiltrating immune cells.