Despite the efforts of researchers to develop effective cancer vaccines clinical trials have in the most part been disappointing. Dendritic cells represent a key component of cancer immunotherapy and are the most potent antigen presenting cells known, uniquely capable of inducing immunity to newly introduced antigens. Immunologists have attempted to harness the considerable therapeutic potential of these cells either through the development of antigen vaccines which stimulate endogenous dendritic cells or the use of dendritic cells which have been loaded and matured ex vivo with cancer antigens.
Normally, dendritic cells reside as immature cells in peripheral tissues however under certain conditions they take up and process antigens and also undergo activation and maturation. Mature cells prime specific CD4 and CD8 T cells to these antigens. Tumors however are characterized by the presence of immature dendritic cells that are unable to stimulate T cells. Defects in dendritic cell maturation and activation may prevent effective antitumor responses and may even induce immune tolerance.
In order to improve dendritic cell vaccines a number of strategies have been employed including attempts to stimulate pathways that induce maturation. Most commonly this has been done ex vivo using various cytokines including GM-CSF, IL-4, TNF alpha, IL-6 and IL-1 beta. In addition to being cumbersome and costly this approach appears to be far from optimal. In their December Nature Biotechnology publication Lei Shen et al from Baylor College of Medicine have taken the opposite and novel route of inhibiting endogenous mechani
SOCS1 functions as a negative modulator of multiple cytokines and recent studies have shown that dendritic cells that fail to express SOCS1 show increased immunogenicity. In their study Shen et al employed siRNA technology to block SOCS1, an approach which increased the response of dendritic cells to LPS activation as well as their ability to elicit a specific cytotoxic T cell response to antigen-prepulsed dendritic cells. Transfection of dendritic cells with SOCS1 siRNA using engineered lentivirus was a particularly effective way of silencing SOCS1 in dendritic cells. This is important since it enable the effects of SOC1 silencing to be investigates more reliably in proof of concept studies but it also suggests that viral transfection of dendritic cells with siRNA for SOCS1 being prepared for clinical use will be a viable approach. Of note, Biovex, one of the leaders in oncolytic virus development have developed ImmunoVEX, an HSV virus that has been engineered to deliver multiple antigens to dendritic cells. Further development of this approach to use viruses to simultaneously load dendritic cells with antigen and siRNA SOCS1 would offer a one step approach to preparing cancer vaccines.
Dendritic cells transfected with SOCS1 siRNA and prepulsed with an antigen increased antigen specific T cell responses in vivo when administered to mice. This did not simply reflect an increased maturation of the dendritic cells, rather it appeared to be due to and increase in the immunogenic state of the cells irrespective of their stage of maturity. SOCS1 silencing appeared to lower the threshold for antigen stimulation and furthermore in mature cells it also apparently prevented the development of tolerance upon continuous antigen stimulation. This is important therapeutically; prolonged exposure of dendritic cell vaccine to tumor antigen could be expected to produce a diminished clinical effects due to tolerance. Limiting the development of tolerance could therefore extend the anti-cancer efficacy. Shen et al did in fact report that SOCS1 silencing significantly enhanced the anti-cancer effect of dendritic cells. When mice were inoculated with B16 melanoma cells, tumors rapidly expanded in size. Matured dendritic cells pre-pulsed with an antigen expressed by B16 cells, tyrosine-related protein (TRP) 2, had little effect on tumor growth. In sharp contrast pre-pulsed dendritic cells in which SOCS1 was silenced completely abolished tumor growth. This was suggested to result from an increased immunogenicity of mature dendritic cells.
This important study suggests that SOCS1 plays an important role in negatively regulating antigen presentation by dendritic cells. Blocking this regulatory pathway can increase antigen presentation translating to a dramatically increased therapeutic efficacy in the context of tumor growth. Enhancing the therapeutic activity of antigen loaded dendritic cells by blocking endogenous inhibitory pathways is likely to represent a much simpler approach than mimicking endogenous stimulatory pathways. CTLA-4 expressed by activated T cells represents one endogenous inhibitory pathway and indeed neutralizing anti-CTLA-4 antibodies have been evaluated in the clinic. This indirect approach to modulating dendritic cell activity appears to produce excessive adverse effects. SOCS1 inhibition on the other hand directly affects dendritic cell activity offer a much more selective means of boosting the anti-cancer activity of dendritic cells.
RNA interference (RNAi) or gene silencing involves the use of double stranded RNA (dsRNA). Once inside the cell, this material is processed into short 21-26 nucleotide RNAs termed siRNAs that are used in a sequence-specific manner to recognize and destroy complementary RNA, in this case that coding for RNA. siRNAs can be delivered to cells in culture by electroporation or by transfection using pla
As a final point, in June 2004
Last updated on: 27/08/2010 11:40:18
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