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: Ankur Singh, Hong Qin, Irina Fernandez, Jinsong Wei, Jian Lin, Larry W Kwak, Krishnendu Roy
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 155 Issue 2 Pg. 184-92 (Oct 30 2011) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 21708196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Chemokines
• Cross-Linking Reagents
• Delayed-Action Preparations
• Drug Carriers
• Hydrogels
• Immunoglobulin Idiotypes
• RNA, Small Interfering
• Interleukin-10
• DNA

Topics

• Animals
• Antigens, Neoplasm (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (administration & dosage, immunology)
• Chemokines (administration & dosage, immunology)
• Cross-Linking Reagents
• DNA (administration & dosage, immunology)
• Delayed-Action Preparations
• Dendritic Cells (cytology, immunology)
• Drug Carriers (chemistry)
• Female
• Hydrogels
• Immunoglobulin Idiotypes (immunology)
• Injections, Intramuscular
• Interleukin-10 (immunology)
• Lymphoma, B-Cell (immunology, therapy)
• Mice
• Mice, Inbred BALB C
• RNA, Small Interfering (administration & dosage, immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• Th1 Cells (cytology, immunology)