Innovative Strategy Enhances CAR T Cell Therapy for Glioblastoma Treatment

A groundbreaking study by researchers from the San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET) in Milan, led by Nadia Coltella and Luigi Naldini, has unveiled a promising strategy to enhance the effectiveness of chimeric antigen receptor (CAR) T cell therapy for glioblastoma, one of the most aggressive and treatment-resistant brain tumors. The findings, published in the prestigious journal *Science Translational Medicine* on July 3, 2025, reveal how gene therapy can target immune-stimulating cytokines to the tumor microenvironment (TME), thereby rejuvenating CAR T cell activity and improving immune responses against tumor growth.

The study addresses a significant challenge in cancer therapy: the hostile and immunosuppressive environment of solid tumors like glioblastoma, which has historically rendered CAR T cells less effective. "Solid tumors like glioblastoma have been notoriously difficult for CAR T cells to penetrate and control," explains Dr. Francesca Rossari, the first author of the study. The team’s innovative approach involves reprogramming tumor-infiltrating macrophages to deliver cytokines directly to the tumor, effectively transforming the TME into a supportive environment for immune cells. This is critical, as CAR T cells have demonstrated significant success in treating blood cancers but have faced hurdles in solid tumor therapies due to their immunosuppressive surroundings.

The strategy detailed in the study leads to the targeted release of two cytokines: interferon-α (IFN-α) and a mutant form of interleukin-2, specifically designed to activate a cognate mutant receptor introduced into CAR T cells. The selective delivery of IFN-α aims to counteract local immunosuppressive signals and enhance the activity of immune effectors, while the engineered interleukin-2 promotes the proliferation of CAR T cells engaged in tumor attack. "The cross-talk between genetically engineered macrophages and CAR T cells established in the TME ensures that immune stimulants act only where needed, thereby minimizing systemic toxicity," notes Dr. Alvisi, co-first author of the study.

In preclinical glioblastoma models, the targeted cytokine therapy successfully rescued CAR T cell activity, which had previously been ineffective when administered alone. Notably, the combination therapy not only delayed tumor progression but also extended survival in the treated mice. The study also found that even tumors with only a fraction of cells expressing the CAR-targeted antigen B7-H3 were effectively controlled, indicating a broader immune activation that included the host's own T cells.

"This phenomenon, known as antigenic spreading, is crucial for generating effective immunity as it addresses immune evasion by tumors that present only a single antigen," explains Dr. Coltella. The implications of this research are significant, as it represents a potential leap forward in the treatment of glioblastoma, which has long evaded effective therapeutic interventions.

Luigi Naldini, director of SR-TIGET and a professor at Università Vita-Salute San Raffaele, emphasized the importance of this research, stating, "This work marks another significant advancement in our commitment to develop novel gene and cell therapy strategies against tumors, similar to our successes in treating various genetic diseases."

The tumor-targeted IFN-α delivery strategy is currently being evaluated in a first-in-human phase 1/2a trial (Temferon trial) led by Genenta Science, a biotech company that emerged from SR-TIGET and is now publicly traded on NASDAQ. Initial results indicate feasibility, safety, and biological activity in reprogramming the TME, although the therapeutic benefit has so far been limited by the small number of treated patients. Future studies may explore the combination of Temferon with CAR T cell administration to enhance treatment efficacy further.

This innovative approach not only holds potential for glioblastoma treatment but may also serve as a model for developing therapies against other solid tumors, thereby broadening the impact of CAR T cell technologies in oncology. The results of this research highlight a significant step forward in the ongoing battle against some of the most challenging forms of cancer, promising hope for improved patient outcomes in the future.