Scientists have developed a groundbreaking therapeutic approach for treating glioblastoma, the most aggressive type of brain cancer. They engineered specialized molecules known as trispecifics that link cancer-fighting T cells to two distinct receptors associated with brain cancer.
Dr. David B. Weiner, Ph.D., who is the Executive Vice President, director of the Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Distinguished Professor in Cancer Research at The Wistar Institute, along with his team, has successfully tested a new immune therapy. In initial lab trials, this therapy consistently enhanced survival rates and reduced tumor size in glioblastoma cases. Their research was published in the paper titled “Novel tri-specific T-cell engager targeting IL-13Rα2 and EGFRvIII provides long-term survival in heterogeneous GBM challenge and promotes antitumor cytotoxicity with patient immune cells,” in the Journal for ImmunoTherapy of Cancer.
“This research employs an innovative strategy to create a glioblastoma-targeting ‘trispecific’ antibody, which could potentially be produced within the patients themselves for glioblastoma treatment in the future,” explained Dr. David Weiner, the corresponding author. “We are optimistic that this approach could help prevent tumor escape mechanisms that hinder treatment responses in various cancers.”
Glioblastoma is the most lethal brain cancer, with a survival rate of less than 5% over five years. The grim prognosis is largely due to the tumor’s inherent ability to suppress the immune system coupled with its diverse nature—both of which severely limit the immune system’s effectiveness against glioblastoma.
All cancers, particularly fast-growing and immune-silent types like glioblastoma, produce specific signals known as antigens that researchers can use in immune therapies to alert the immune system about hidden tumors. However, creating an effective immune therapy for glioblastoma is particularly tough due to the significant variability of glioblastoma antigens. This diversity means that any successful immune therapy needs to deliver extensive information to the immune system.
The researchers crafted a distinct trispecific antibody incorporated into a DNA-based delivery mechanism. Their DNA-encoded trispecifics, referred to as “DTriTEs,” connected cancer-killing T cells via the CD3 protein to two specific glioblastoma antigens: the IL-13Rα2 protein and the EGFRvIII protein. This connection enables the immune system’s T cells to be effectively activated upon encountering various glioblastoma tumors exhibiting either or both of these antigens.
During laboratory tests, one particular DTriTE configuration demonstrated exceptional anticancer effectiveness. It not only significantly activated cancer-fighting T cells but also engaged another type of tumor-fighting cell known as Natural Killer (NK) T cells. This DTriTE design proved to be the most potent treatment, achieving sustained survival and tumor control in all glioblastoma model tests conducted throughout the study. In a prolonged challenge model aimed at assessing the durability of DTriTE’s anti-cancer response, 66% of the models treated with the DTriTE experienced lasting tumor suppression and survival—an achievement unmatched by any other treatment they compared it with.
“Our preliminary findings indicate that even for a cancer resistant to treatment like heterogeneous glioblastoma, the novel DTriTE design can provoke a powerful and enduring anticancer response, potentially adding a new strategy to our collection of treatment options,” remarked Daniel H. Park, the paper’s lead author and a Ph.D. student in Weiner’s lab. “We are eager to build upon these designs for possible glioblastoma treatments and, in the future, to explore their application to other cancer types that have not responded well to immunotherapy due to similar immune challenges.”
