Transmorphic phage-guided systemic delivery of TNFα gene for the treatment of human pediatric medulloblastoma

Medulloblastoma is the most common childhood brain tumor with an unfavorable prognosis and limited options of harmful treatments that are associated with devastating long-term side effects. Therefore, the development of safe, noninvasive, and effective therapeutic approaches is required to save the quality of life of young medulloblastoma survivors. We postulated that therapeutic targeting is a solution. Thus, we used a recently designed tumor-targeted bacteriophage (phage)-derived particle, named transmorphic phage/AAV, TPA, to deliver a transgene expressing the tumor necrosis factor-alpha (TNFa) for targeted systemic therapy of medulloblastoma. This vector was engineered to display the double-cyclic RGD4C ligand to selectively target tumors after intravenous administration. Furthermore, the lack of native phage tropism in mammalian cells warrants safe and selective systemic delivery to the tumor microenvironment. In vitro RGD4C.TPA.TNFa treatment of human medulloblastoma cells generated efficient and selective TNFa expression, subsequently triggering cell death. Combination with the chemotherapeutic drug cisplatin used clinically against medulloblastoma resulted in augmented effect through the enhancement of TNFa gene expression. Systemic administration of RGD4C.TPA.TNFa to mice-bearing subcutaneous medulloblastoma xenografts resulted in selective tumor homing of these particles and consequently, targeted tumor expression of TNFa, apoptosis, and destruction of the tumor vasculature. Thus, our RGD4C.TPA.TNFa particle provides selective and efficient systemic delivery of TNFa to medulloblastoma, yielding a potential TNFa anti-medulloblastoma therapy while sparing healthy tissues from the systemic toxicity of this cytokine.

Automated summary

Medulloblastoma is a common childhood brain tumor with limited treatment options and poor prognosis. Researchers have developed a tumor-targeted bacteriophage-derived particle called TPA to deliver a gene expressing the tumor necrosis factor-alpha (TNFa) for targeted therapy of medulloblastoma. In vitro and in vivo experiments showed that the TPA particle effectively and selectively delivered TNFa to medulloblastoma, leading to cell death and destruction of tumor blood vessels.