RNA-Modified T Cells Mediate Effective Delivery of Immunomodulatory Cytokines to Brain Tumors.

Abstract

With the presence of the blood-brain barrier (BBB), successful immunotherapeutic drug delivery to CNS malignancies remains a challenge. Immunomodulatory agents, such as cytokines, can reprogram the intratumoral microenvironment; however, systemic cytokine delivery has limited access to the CNS. To bypass the limitations of systemically administered cytokines, we investigated if RNA-modified Tcells could deliver macromolecules directly to brain tumors. The abilities of Tcells to cross the BBB and mediate direct cytotoxic killing of intracranial tumors make them an attractive tool as biological carriers. Using Tcell mRNA electroporation, we demonstrated that activated Tcells can be modified to secrete granulocyte macrophage colony-stimulating factor (GM-CSF) protein while retaining their inherent effector functions invitro. GM-CSF RNA-modified Tcells effectively delivered GM-CSF to intracranial tumors invivo and significantly extended overall survival in an orthotopic treatment model. Importantly, GM-CSF RNA-modified Tcells demonstrated superior anti-tumor efficacy as compared to unmodified Tcells alone or in combination with systemic administration of recombinant GM-CSF. Anti-tumor effects were associated with increased IFN-γ secretion locally within the tumor microenvironment and systemic antigen-specific Tcell expansion. These findings demonstrate that RNA-modified Tcells may serve as a versatile platform for the effective delivery of biological agents to CNS tumors.