Innovative Cell Cross-Talk Enhances CAR-T Therapy Against Glioblastoma

Researchers from the San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET) in Milan have developed a groundbreaking approach to improve the efficacy of chimeric antigen receptor (CAR) T cell therapy for glioblastoma, one of the most aggressive and treatment-resistant brain tumors. Led by Nadia Coltella and Luigi Naldini, the team devised a strategy to reprogram tumor-infiltrating macrophages to deliver immune-stimulating cytokines directly into the tumor microenvironment (TME). This targeted cytokine release helps convert the immunosuppressive TME into a more supportive environment for immune cells.

The key cytokines involved are interferon-α (IFN-α), which enhances immune activation and antigen presentation, and a specially engineered mutant of interleukin-2 (IL-2) that specifically activates T cells expressing a co-introduced mutant receptor. This selective activation boosts the proliferation and activity of the effector cells fighting the tumor, while minimizing systemic toxicity.

Published in Science Translational Medicine, the study demonstrates how targeting the immune-stimulating cytokines to the TME restores CAR-T cell activity that is often lost in solid tumors due to their hostile environment. In preclinical glioblastoma models, this approach not only delayed tumor growth but also extended survival by engaging endogenous T cells and promoting antigen spreading — a phenomenon where the immune response broadens to target multiple tumor antigens.

The research builds on previous gene therapy techniques that involve genetically engineering hematopoietic progenitors to generate monocytes/macrophages capable of releasing therapeutic payloads within tumors. This strategy has already entered early clinical trials, notably the Temferon trial by Genenta Science, which explores delivering IFN-α as a standalone therapy for glioblastoma. Early results indicate the safety and biological activity of this approach, suggesting that combining it with CAR-T therapy could further improve treatment outcomes.

Dr. Rossari emphasizes that this method enables precise cytokine delivery directly to the tumor site, enhancing the persistence and activation of CAR-T cells and recruiting the body's own immune cells. This balanced approach aims to overcome the challenges faced in treating solid tumors with CAR-T cells, which are typically limited by the immunosuppressive TME.

In summary, this innovative approach of engineered cell cross-talk represents a significant advancement in the fight against glioblastoma, potentially paving the way for more effective, targeted therapies that harness the power of the immune system to combat resistant cancers.