Researchers from the Wistar Institute developed a novel immunotherapy that improves survival rates and reduces tumor burden in preclinical models of glioblastoma (GBM).
The study highlights an innovative approach to tackling GBM’s notorious resistance to treatment. Unlike many other cancers, GBM exhibits extreme antigenic heterogeneity, meaning its tumor cells present a wide variety of markers that make it difficult for the immune system to target effectively. Current monospecific immunotherapies often fail to address this diversity, allowing tumors to evade immune responses.
To overcome glioblastoma’s complexity, the team developed a DNA-encoded trispecific T-cell engager (DTriTE), a next-generation antibody that links immune T cells to tumor cells by targeting two key glioblastoma antigens: EGFRvIII and IL-13Rα2. By simultaneously engaging the CD3 protein on T cells, the therapy prompts a robust immune attack against glioblastoma cells expressing either or both of these antigens. The findings were published in the Journal for ImmunoTherapy of Cancer.
Promising results in preclinical models
The researchers tested three DTriTE designs, each featuring a unique arrangement of antigen-binding domains. One construct, named DT2035, outperformed the others in preclinical studies. Laboratory tests demonstrated that DT2035 effectively activated T cells, leading to increased production of cancer-fighting cytokines like interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2).
The therapy’s success extended to animal models. In a challenging heterogeneous glioblastoma model mimicking the complexity of human tumors, DT2035 eliminated tumor burden in 100% of models for the duration of the study and extended survival significantly, with 66% of treated subjects showing long-term tumor control over 120 days.
Dual action: Engaging T cells and NKT cells
In addition to activating T cells, DT2035 also stimulated natural killer T (NKT) cells, a crucial component of the immune system that bridges innate and adaptive immunity. NKT cells play a pivotal role in enhancing the overall immune response, rapidly producing cytokines and exerting direct tumor-killing effects.
“Our data show that, even for a cancer as resistant to treatment as heterogenous glioblastoma, the novel DTriTE design can induce a potent and lasting anticancer response, potentially adding a new tool to our arsenal of approaches,” said first author Daniel H. Park. “We’re excited to continue to expand on these designs for potential treatment of glioblastoma and, in the future, for other types of cancer that haven’t responded to immunotherapy due to similar immune issues.”
A step toward clinical applications
The researchers also evaluated DT2035 using immune cells derived from glioblastoma patients. Even in cases where prior treatments like chemotherapy and radiation had weakened patients’ immune systems, the therapy demonstrated robust tumor-killing activity. This translational relevance suggests DT2035 could be a valuable option for patients who have already undergone extensive treatment.
Moreover, RNA sequencing of DT2035-activated T cells revealed significant upregulation of genes linked to cytotoxicity, proliferation, and immune modulation. This suggests that the therapy not only activates immune cells but also primes them for sustained antitumor activity.
The Wistar team’s findings underscore the potential of DTriTEs to address antigenic heterogeneity in glioblastoma and other cancers with similar challenges. Unlike traditional protein-based antibody treatments, which often require frequent dosing, DT2035’s DNA-encoded delivery enables sustained expression and prolonged therapeutic effects. “This extended therapeutic window may suggest an enhanced overall efficacy of the treatment by maintaining continuous pressure on the tumor,” they noted.
Future work will focus on refining the therapy’s design, assessing its safety and efficacy in more complex models, and exploring its potential synergy with existing immunotherapies such as checkpoint inhibitors.
