EXTH-106. Oncolytic adenovirus armed with immune stimulators: a promising partner for CAR T cell therapy in primary and metastatic malignant brain tumors

作者：Hong Jiang, Jiasen He, Alejandra Duran, Xuejun Fan, Dong Ho Shin, Maria Frost, Akhila Parthasarathy, Andrés López-Rivas, Andrew G. Gillard, Joy Gumin, Frederick F. Lang, Candelaria Gomez‐Manzano, Juàn Fueyo · 发表于：Neuro-Oncology · 年份：2025 · DOI：10.1093/neuonc/noaf201.1439 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Immune Cell Function and Interaction

Abstract Advanced solid tumors pose significant clinical challenges due to a heterogeneous and immunosuppressive tumor microenvironment, which limits the efficacy of approved therapies. Based on promising clinical trial results with the oncolytic adenovirus (OA) Delta-24-RGD in glioma patients, we previously demonstrated that Delta-24-RGDOX, engineered to express the immune co-stimulatory molecule OX40 ligand (OX40L), enhances local and systemic anti-tumor immunity via an in situ autovaccination effect in immunocompetent mice bearing orthotopic intracranial (i.c.) gliomas or disseminated subcutaneous (s.c.)/i.c. melanomas. To further enhance therapeutic efficacy, we developed Delta-24-RGDOX-IL15, a novel OA co-expressing IL-15 and OX40L. IL-15 is known to activate NK and T cells and support the persistence of CD8⁺ memory T cells. Delta-24-RGDOX-IL15 maintained robust viral replication and oncolytic activity comparable to its predecessors and more effectively stimulated T cell responses, including CAR T cells, against cancer cells expressing corresponding tumor-associated antigen. In C57BL/6 mice bearing syngeneic GD2-expressing tumors, including i.c. gliomas or disseminated s.c./i.c. melanomas, intratumoral delivery of Delta-24-RGDOX-IL15 into the i.c. glioma or s.c. melanoma significantly reduced microglia and myeloid cell frequency while increasing T cell frequency and activation of NK, dendritic, and T cells within the tumor-bearing brain hemisphere from the mice of the tw...