title: An injectable synthetic immune-priming center mediates efficient T-cell class switching and T-helper 1 response against B cell lymphoma.
abstract: Patients with malignant non-Hodgkin's lymphomas (NHL) of B-cell lineages relapse despite initial anti-tumor response to chemotherapy or antibody treatments. Failure to eliminate the tumor is often because of inadequate priming, low cell numbers and suboptimal phenotype of effector T cells. Here we describe a new biomaterial-based controlled-release paradigm to treat weakly immunogenic NHLs by in-situ amplifying the number of functional, antigen-specific T-helper 1 (Th1) cells following immunotherapy. An injectable, synthetic immune priming center (sIPC) consisting of an in-situ crosslinking, chemokine-carrying hydrogel and both DNA- and siRNA dual-loaded microparticles, is reported. This sIPC chemo attracts a large number of immature dendritic cells (DCs) at the site of administration and efficiently co-delivers both DNA antigens and interleukin-10 (IL10)-silencing siRNA to those cells. Using a murine model of A20 B cell lymphoma, we demonstrate that combination of DNA-antigen delivery and IL10 silencing, synergistically activate recruited immature DCs and cause a strong shift towards Th1 response while suppressing Th2 and Th17 cytokines. sIPC-based immunotherapy showed 45% more CD8+ cytotoxic T cell (CTL) response and 53% stronger CD4+ CTL activity compared to naked DNA vaccine. In addition, in-vivo sIPC immunization induced significant protection (p<0.01) against subsequent tumor challenge. Such a multi-modal, injectable system that simultaneously delivers chemokines, siRNA and DNA antigens to DCs marks a new approach to in-situ priming and modulation during immunotherapy and could provide effective vaccination strategies against cancers and infectious diseases.
authors.affiliation: Department of Biomedical Engineering, The University of Texas, Austin, TX 78712, USA.
authors.forename: Ankur
authors.initials: A
authors.lastname: Singh
authors.forename: Hong
authors.initials: H
authors.lastname: Qin
authors.forename: Irina
authors.initials: I
authors.lastname: Fernandez
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wei
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Roy
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D018925:Chemokines / Q000008:administration & dosage* / Q000276:immunology; D003432:Cross-Linking Reagents; D004247:DNA / Q000008:administration & dosage* / Q000276:immunology; D003692:Delayed-Action Preparations; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D020100:Hydrogels; D007130:Immunoglobulin Idiotypes / Q000276:immunology; D007273:Injections, Intramuscular; D016753:Interleukin-10 / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018925:Chemokines; D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020100:Hydrogels; D007130:Immunoglobulin Idiotypes; D034741:RNA, Small Interfering; D016753:Interleukin-10; D004247:DNA