Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. With rapid growth, early spread along the white matter of the brain, and a high recurrence rate after surgery, GBM has an extremely poor prognosis. The median survival time for most patients after diagnosis is less than 15 months, and the five – year survival rate is lower than 5%. However, in recent years, several triple – therapy strategies have emerged as new hopes for extending the lifespan of GBM patients.
Scientists at the Johns Hopkins Kimmel Cancer Center conducted a study showing that a triple – therapy regimen for GBM, combining two immunotherapies with targeted radiotherapy, can significantly prolong the survival of mice with brain cancer. Mice receiving the triple therapy survived an average of 67 days after being implanted with murine GBM cells, compared to only 24 days for those receiving just the two immunotherapies. Half of the mice in the triple – therapy group survived 100 days or more, and when cancer cells were re – injected subcutaneously, they could resist the formation of new tumors. In this therapy, one immunotherapy uses antibodies to bind and block the CTLA – 4 molecule on T cells, allowing T cells to infiltrate and fight tumor cells. The other immunotherapy, 4 – 1BB, provides a positive “activation” signal to stimulate anti – tumor T cells.
A research team from the University of Sydney proposed an immune “triple – therapy” that combines PD – 1 inhibitors, CTLA – 4 inhibitors, and LAG – 3 inhibitors. In a study of a patient with IDH wild – type, MGMT promoter non – methylated GBM (a molecular subtype with poor prognosis), the patient received a course of immune neoadjuvant “triple – therapy” before tumor resection, followed by adjuvant local radiotherapy (60 Gy/30 fractions), continuous immunotherapy, and personalized antigen peptide treatment after surgery. The results were remarkable: after treatment, the number of CD3+CD4/CD8 – positive T cells infiltrating the tumor increased significantly and were in an activated state, while the number of immunosuppressive macrophages and microglia decreased significantly. The patient’s recurrence – free survival time extended to 17 months, breaking previous limitations in treatment efficacy.
Researchers at Brown University developed a triple – therapy (IRT) that combines a new class of drugs called imipridones with radiotherapy and standard chemotherapy. In experiments on tumor cells cultured in the laboratory and mice implanted with human GBM tumors, the IRT combination slowed tumor growth, reduced the number of cancer cells, and extended the survival of the mice. The median survival time of mice receiving triple therapy was 123 days, and some even survived for more than 200 days, compared to 44 – 103 days for those receiving only one or two treatments. Additionally, the drugs in this therapy can cross the blood – brain barrier, interfere with the mitochondrial function of cancer cells, reduce the levels of molecules that support tumor growth and immune evasion, and increase the levels of molecules involved in the immune response. They can also decrease the level of MGMT, making tumors more sensitive to the chemotherapy drug temozolomide (TMZ).
A clinical trial conducted by NovoCure, an American company specializing in electric field therapy, combined tumor – treating fields (TTFields), the PD – 1 inhibitor pembrolizumab, and temozolomide for the treatment of adult patients with newly diagnosed GBM. Among the 25 enrolled patients who received surgery, standard radiotherapy, and chemotherapy followed by the triple – therapy regimen, in 19 evaluable patients, the median progression – free survival (PFS) reached at least 11.2 months, nearly doubling compared to historical control study data (6.7 months), and 24% of the patients achieved partial or complete remission.
These research findings demonstrate that triple – therapy strategies work synergistically through different mechanisms. They effectively enhance the immune system’s ability to recognize and attack tumors, reshape the tumor immune microenvironment, and overcome the limitations of single – therapy approaches, significantly improving the survival prospects of GBM patients. Although some of these studies are still in the pre – clinical or small – scale clinical trial stage, they have shown great potential, bringing new directions and hopes for GBM treatment. It is expected that these strategies will promote the innovation of GBM treatment models and bring longer survival times and better quality of life to patients.
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