New Trispecific Immunotherapy Shows Potential Against Glioblastoma

Glioblastoma, the most aggressive form of brain cancer, has long resisted meaningful advances in treatment, with a five-year survival rate of less than 5%. However, researchers at The Wistar Institute have unveiled a novel immune therapy that may offer hope for combating this deadly disease. In preclinical studies, the therapy significantly improved survival and reduced tumor burden in glioblastoma models. The findings, published in the Journal for ImmunoTherapy of Cancer, suggest that this innovative approach could overcome critical barriers to effective treatment.

A Unique Approach to a Complex Challenge

The therapy, described as a "trispecific" antibody encoded using DNA technology, is designed to target glioblastoma’s inherent complexity. Glioblastoma tumors are known for their immunosuppressive environment and heterogeneity, which make it difficult for immune therapies to recognize and attack them effectively. To address this, the Wistar team engineered DNA-encoded trispecific T-cell engagers, or "DTriTEs." These molecules link T cells—the immune system's cancer-killing soldiers—to two glioblastoma-specific antigens, IL-13Rα2 and EGFRvIII. By engaging both antigens, the DTriTEs enhance the immune system's ability to detect and destroy diverse glioblastoma cells.

In preclinical testing, the DTriTE design demonstrated remarkable efficacy, activating both T cells and Natural Killer (NK) T cells, another type of tumor-fighting immune cell. This dual activation provided durable tumor control in 100% of tested models. Moreover, in a long-term challenge study, 66% of treated models exhibited sustained tumor suppression, a milestone no other therapies achieved in this study.

Why It Matters

The potential impact of this development extends beyond glioblastoma. Immunotherapy has struggled against cancers like glioblastoma that evade detection by the immune system due to their variability and immunosuppressive nature. The DTriTE approach addresses these challenges by delivering complex and comprehensive instructions to the immune system, ensuring that even highly heterogeneous tumors are targeted.

“Even for a cancer as resistant to treatment as heterogeneous glioblastoma, the novel DTriTE design can induce a potent and lasting anticancer response,” said Daniel H. Park, Ph.D. student and lead author of the study. The researchers believe this platform could be adapted to treat other cancers that have historically been unresponsive to immunotherapy, opening the door to broader applications in oncology.