title: Tipping a favorable CNS intratumoral immune response using immune stimulation combined with inhibition of tumor-mediated immune suppression.
abstract: High-grade gliomas are notoriously heterogeneous regarding antigen expression, effector responses, and immunosuppressive mechanisms. Therefore, combinational immune therapeutic approaches are more likely to impact a greater number of patients and result in longer, durable responses. We have previously demonstrated the monotherapeutic effects of miR-124, which inhibits the signal transducer and activator of transcription 3 (STAT3) immune suppressive pathway, and immune stimulatory 4-1BB aptamers against a variety of malignancies, including genetically engineered immune competent high-grade gliomas. To evaluate potential synergy, we tested an immune stimulatory aptamer together with microRNA-124 (miRNA-124), which blocks tumor-mediated immune suppression, and found survival to be markedly enhanced, including beyond that produced by monotherapy. The synergistic activity appeared to be not only secondary to enhanced CD3(+) cell numbers but also to reduced macrophage immune tumor trafficking, indicating that a greater therapeutic benefit can be achieved with approaches that both induce immune activation and inhibit tumor-mediated immune suppression within the central nervous system (CNS) tumors.
authors.affiliation: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.affiliation: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Neuropathology, University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.affiliation: Department of Microbiology & Immunology, University of Miami Miller School of Medicine , Miami, FL, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Schrand
authors.affiliation: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Gabrusiewicz
authors.affiliation: Biostatistics, University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Shouhao
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.affiliation: Experimental Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: George
authors.initials: G
authors.lastname: Calin
authors.affiliation: Department of Microbiology & Immunology, University of Miami Miller School of Medicine , Miami, FL, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Gilboa
authors.affiliation: Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
keywords: Aptamer; CNS; STAT3; gliomas; microRNA