Glioblastoma Cell Derived Exosomes as a Potent Vaccine Platform Targeting Primary Brain Cancers and Brain Metastases

Abstract

Glioblastoma multiforme (GBM) is the most prevalent brain tumor that remains incurable up to now. The rapid advancement of immunotherapy makes vaccines a promising therapeutic approach for GBM. However, current vaccine platforms, such as peptides, dendritic cells, mRNA, and viral vectors, are subject to limitations such as inadequate antigen loading, insufficient immune system activation, ineffective vector delivery, complicated fabrication process, and complex formulation. Here, we developed a GBM tumor cell derived homologous exosomal nanovaccine that does not need to carry any additional tumor antigens and leads to the activation of antigen-presenting cells (APCs) in lymph nodes, increasing the proportion of immune cells (matured dendritic cells, cytotoxic T cells, and memory T cells) and in turn promoting the expression of cytokines (TNF-α, IL-6, and IFN-γ), which effectively stimulates innate immunity to trigger durable protective immunity against tumor cell insult. Our nanovaccine platform possesses efficient dual-targeting capability to lymph nodes and the brain. More importantly, the developed exosomal nanovaccines protected 100% of treated mice by inducing sustained and strong immunity against GL261-luc GBM tumor cells, resulting in 100% mouse survival (8/8) up to 5 months. Our nanovaccines also induced antitumor immune responses in the immunosuppressed CT2A-luc GBM mouse model with greatly improved survival compared to control mice. Exosomal nanovaccines also demonstrated effectiveness in preventing brain metastasis in the B16F10-luc melanoma malignant brain metastasis mouse model, and the mice showed notably improved survival rates. Our simple and potent exosomes offer a versatile platform for clinical translation as individualized vaccine therapy.