CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a po-tential treatment method, but it is often hindered by poor infil-tration of CAR-T cells in tumors and highly immunosuppres-sive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to in-crease the infiltration of CAR-T cells and reprogram the immu-nosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), reg-ulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus re-vealed that CXCL11-armed oAd can improve immune-viro-therapy and can be a promising adjuvant of CAR-T therapy for GBM.

Automated summary

Glioblastoma (GBM) is a highly aggressive primary malignant brain cancer that requires effective treatment. Chimeric antigen receptor T (CAR-T) cell therapy shows potential, but its efficacy is hindered by poor infiltration of CAR-T cells in tumors and an immunosuppressive tumor microenvironment (TME). This study demonstrates that arming an oncolytic adenovirus (oAds) with CXCL11 increases CAR-T cell infiltration and reprograms the immunosuppressive TME, thus improving therapeutic efficacy.