Tumor-Targeted Delivery of IL-2 by NKG2D Leads to Accumulation of Antigen-Specific CD8+ T Cells in the Tumor Loci and Enhanced Anti-Tumor Effects

Interleukin-2 (IL-2) has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein) or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci

Chemokines and TRANCE as genetic adjuvants for a DNA vaccine to rabies virus

An adaptive immune response is initiated by mature dendritic cells presenting processed antigen to naïve T cells. Assuming that the magnitude of the immune response is influenced by the number and type of antigen-presenting dendritic cells and by the duration of antigen presentation, we tested if chemokines that bind to receptors expressed on immature dendritic cells or TRANCE, a survival factor for mature dendritic cells, can serve as adjuvants. None of the immunomodulaters given as genetic adjuvants with a DNA vaccine encoding the full-length rabies virus glycoprotein augmented the transgene product-specific response. However, RANTES, MCP-1, MIP 1-β, and TRANCE given together with a DNA vaccine expressing a truncated and thus secreted version of the rabies virus glycoprotein enhanced the response suggesting that the tested genetic adjuvants promoted preferentially presentation of reprocessed antigen originating from transduced tissue cells. © 2003 Elsevier Inc. All rights reserved