Targeted delivery of tumor necrosis factor in combination with chemotherapy effectively prolongs survival of brain tumor patients
Glioblastoma (GBM) is the most common and deadly brain tumor. Because of their extremely high malignancy and rapid progression, the vast majority of patients have a very poor prognosis—the median survival of glioblastoma patients is only about 15 months after surgery, radiotherapy, and other treatments, with a five-year survival rate of less than 5%.
The current standard of care for newly diagnosed glioblastoma includes maximum safe surgical resection followed by radiotherapy with temozolomide. At the time of disease progression, lomustine (CCNU) is considered the most appropriate treatment. In fact, the overall objective effectiveness of CCNU for recurrent glioblastoma ranges from 4.3% to 13.9%, while the complete remission rate is less than 1.3%. Other therapeutic strategies, such as anti-VEGF monoclonal antibody or anti-PD-1 monoclonal antibody, also failed to favor the survival of glioblastoma patients.
Recently, the University of Zurich, Switzerland, and Philogen S.p.A, Italy, published a study in Science Translational Medicine entitled "Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma".
The study shows that L19TNF, an antibody-cytokine fusion protein (ACFP) consisting of human tumor necrosis factor (TNF)-α fused to the L19 antibody (anti-fibronectin), targets tumor neovascularization and that its combination with the chemotherapeutic agent lomustine (CCNU) provides optimal therapeutic effects in a mouse model of glioblastoma in situ.
The team also conducted clinical trials in patients with glioblastoma who had relapsed after standard therapy and showed that the combination of L19TNF and CCNU resulted in objective remission in three of the six patients initially treated and no progression in four at six months.
This study recently reported that certain ACFPs, which target tumor-specific splice variants of neovascularization and fibronectin in the extracellular matrix of solid tumors, including glioblastoma, have antitumor activity in preclinical in situ glioma mouse models. In particular, L19TNF, selectively localizes to tumor neovascularization and is able to prolong the survival of glioma mice and keep a small proportion of mice alive for a long time.
In glioblastoma patients who relapse after standard radiotherapy, L19TNF has the pharmacodynamic effect of treatment-related tumor core necrosis, but marginal tumor cells survive and eventually relapse, thus requiring a more effective therapeutic combination.
The team explored whether L19TNF could act synergistically with PD-1 inhibitors, bevacizumab (VEGF monoclonal antibody), or CCNU for the treatment of recurrent glioblastoma. The results showed that L19TNF in combination with CCNU emerged as the most effective and positive therapeutic combination, and that L19TNF in combination with CCNU was able to cure most of the tumor-bearing mice using an immunocompetent in situ glioblastoma mouse model.
In situ and in vitro immunophenotypic and molecular analyses of mouse models showed that the combination of L19TNF and CCNU induced tumor DNA damage and treatment-related tumor necrosis. In addition, combination treatment upregulated tumor endothelial cell adhesion molecules, promoted immune cell infiltration into tumors, induced immunostimulatory pathways, decreased immunosuppressive pathways, and also increased antigen presentation on MHC class I molecules.
Based on these encouraging preclinical studies, the research team applied the combination of L19TNF and CCNU to patients with glioblastoma.
The team initiated a phase 1/2 clinical trial (NCT04573192) in 6 patients with glioblastoma who progressed to first relapse after standard of care radiotherapy. Preliminary results from this still ongoing clinical trial show that patients have tolerated the combination of L19TNF and CCNU well, with three patients already experiencing objective remission and a median progression-free survival of 43.3 weeks for all patients, significantly longer than progression-free survival with CCNU monotherapy (4–12 weeks), and four of the six patients have not progressed at 6 months.