Abstract 3468: Intratumoral interleukin-7 delivery via human iPS cell-derived neural stem cells for glioblastoma immunotherapy

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor characterized by severe immunosuppression and a poor response to conventional treatments. The immunologically "cold" tumor microenvironment of GBM makes immunotherapy still challenging. Here, we studied the immunostimulatory cytokine interleukin-7 (IL7) for GBM immunotherapy. We first showed that IL7 delivery to GBM tumors effectively induced an immune-active tumor microenvironment and anti-tumor immunity. Next, we developed a therapeutic strategy based on intratumoral IL7 delivery via human iPS cell-derived neural stem cells (iNSCs). This iNSC-IL7 treatment in two mouse syngeneic GBM models (CT2A and GL261) led to robust tumor regression with a complete response rate (CR) of 40%. It also significantly extended the survival of animals with partial responses. This treatment induced an immune-active microenvironment, as evidenced by increasing cytotoxic CD8+ T cell infiltration and activity and established anti-tumor immunity. Following RNA-sequencing analysis, we defined transcriptomic changes of tumors in response to iNSC-IL7 treatment, including various tumor microenvironment modulators and the upregulation of immune checkpoint pathways (e.g., PD-1 and CTLA4). This discovery guided the combination regimens using iNSC-IL7 and immune checkpoint inhibitors (anti-PD1 or anti-CTLA4 monoclonal antibody). These two combination regimens led to CR of 80% (iNSC-IL7 + anti-PD1) and 60% (iNSC-IL7 + anti-CTLA4), more effective than monotherapies (iNSC-IL7: 40%; anti-PD1: 40%; anti-CTLA4: 30%). Our results demonstrate that IL7 is a potent immunostimulatory cytokine for GBM immunotherapy. They support iNSC-IL7 treatment for future clinical translation as an autologous cellular immunotherapy for GBM and likely other solid tumors based on human iPS cell-derived cell progenies. The transcriptomic analysis dataset will facilitate the future development of an optimal iNSC-IL7 therapy through combination strategies with other immunotherapy regimens, such as immune checkpoint inhibitors. Citation Format: Yi Fu, Irfaan Karim, Hernando Lopez-Bertoni, Mingyao Ying. Intratumoral interleukin-7 delivery via human iPS cell-derived neural stem cells for glioblastoma immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3468.