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

• Published in: Molecular therapy 2019-04, Vol.27 (4), p.837-849
• Main Authors: Pohl-Guimarães, Fernanda, Yang, Changlin, Dyson, Kyle A., Wildes, Tyler J., Drake, Jeffrey, Huang, Jianping, Flores, Catherine, Sayour, Elias J., Mitchell, Duane A.
• Format: Article
• Language: English
• Subjects: adoptive cellular therapy; Animals; Antigens; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain cancer; Brain Neoplasms - mortality; Brain Neoplasms - therapy; Brain research; brain tumor; Brain tumors; Cell Line, Tumor; Cell Survival - genetics; Cell- and Tissue-Based Therapy - methods; Cerebrospinal fluid; Clinical trials; Colony-stimulating factor; Cytokines; Cytotoxicity; Disease Models, Animal; Drug delivery; Efficiency; Electroporation; Experiments; Flow cytometry; Gene expression; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Green Fluorescent Proteins - metabolism; Immunoglobulins; Immunomodulation; Immunotherapy; Immunotherapy, Adoptive - methods; Interferon-gamma - biosynthesis; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Macromolecules; Mice; Mice, Inbred C57BL; Mice, Transgenic; mRNA; Original; Proteins; RNA; RNA - genetics; Software; T cells; T-Lymphocytes - metabolism; Transfection - methods; Tumor Microenvironment - genetics; Tumors; Vascular endothelial growth factor; Vectors (Biology); γ-Interferon
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2018.10.007

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 T cells could deliver macromolecules directly to brain tumors. The abilities of T cells to cross the BBB and mediate direct cytotoxic killing of intracranial tumors make them an attractive tool as biological carriers. Using T cell mRNA electroporation, we demonstrated that activated T cells can be modified to secrete granulocyte macrophage colony-stimulating factor (GM-CSF) protein while retaining their inherent effector functions in vitro. GM-CSF RNA-modified T cells effectively delivered GM-CSF to intracranial tumors in vivo and significantly extended overall survival in an orthotopic treatment model. Importantly, GM-CSF RNA-modified T cells demonstrated superior anti-tumor efficacy as compared to unmodified T cells 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 T cell expansion. These findings demonstrate that RNA-modified T cells may serve as a versatile platform for the effective delivery of biological agents to CNS tumors. Biological drug delivery to brain tumors remains a challenge due to the invasive nature of CNS malignancies and a restrictive blood-brain barrier. By genetically modifying T cells with RNA encoding for cytokines, Pohl-Guimarães et al. describe a novel and effective way to deliver immunomodulatory macromolecules locally within intracranial tumors.