Armed Oncolytic Virus Enhances Immune Functions of Chimeric Antigen Receptor-Modified T Cells in Solid Tumors

摘要

The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared to leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus (OV) armed with the chemokine RANTES and the cytokine IL-15, reasoning that the modified OV will have both a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma (NB) as a tumor model we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, while CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, while the intratumoral release of both RANTES and IL-15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor bearing mice. These preclinical data support the use of this innovative biological platform of immunotherapy for solid tumors.