title: Brain tumor immunotherapy with type-1 polarizing strategies.
abstract: Although the safety of vaccine approaches for central nervous system (CNS) malignancies has been established in early phase clinical trials, the success of a vaccine strategy will depend critically on the ability of effector T cells to home in to CNS tumors and durably exert antitumor effects. Based on our recent studies, efficient CNS tumor homing is a characteristic of cytotoxic T lymphocytes (CTLs) with a type 1 phenotype (Tc1), and this appears to be related to the Tc1 response to the type 1 CXC chemokine ligand (CXCL) 10 [also known as interferon (IFN)-inducible protein (IP)-10] and expression of an integrin receptor very late antigen (VLA)-4 on Tc1. In addition, we have previously shown that direct intratumoral delivery of dendritic cells (DCs) ex vivo engineered to secrete IFN-alpha further enhances Tc1 homing via upregulation of CXCL10/IP-10 in the tumor microenvironment. As a means to induce IFN-alpha and CXCL10/IP-10 in the CNS tumor microenvironment in a clinically feasible manner, we used administration of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose (poly-ICLC), a ligand for toll-like receptor 3 and melanoma differentiation-associated gene 5 (MDA5) in combination with vaccinations targeting CTL epitopes derived from glioma-associated antigens (GAAs). The combination of subcutaneous vaccination and i.m. poly-ICLC administration remarkably promoted systemic induction of antigen GAA-specific Tc1s expressing VLA-4 in the CNS tumors and improved the survival of tumor-bearing mice in the absence of detectable autoimmunity. Based on these data, we have implemented a phase I/II vaccination study using type 1 polarizing DCs loaded with GAA peptides in combination with poly-ICLC in patients with recurrent malignant glioma.
authors.affiliation: University of Pittsburgh School of Medicine, Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. okadah@upmc.edu
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005910:Glioma / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D011070:Poly I-C / Q000627:therapeutic use*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012330:RNA, Double-Stranded / Q000276:immunology; D012367:RNA, Viral / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D012330:RNA, Double-Stranded; D012367:RNA, Viral; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C