The development of dendritic cell vaccines to fight cancer is an attractive therapeutic approach. Usually this strategy involves pre-pulsing dendritic cells with cancer antigen and maturing them ex vivo prior to administering them to patients. Limitation in this approach include the cumbersome nature of antigen loading and maturation and the limited immunogenicity of the cells. The company BioVEX have successfully developed viruses to load dendritic cells with antigen. Researchers from Baylor have now made a further leap forward. Rather that mimicking activation pathways they investigated the effects of silencing an inhibitory protein, SOCS1. Silencing SOCS1 using siRNA produced a dramatic increase in dendritic vaccine immunogenicity and anti-cancer efficacy. This study suggests that viruses could be developed to transfect dendritic cells with both antigen and SOCS1 siRNA providing a simple, innexpensive and one step approach to improve cancer vacer vaccines.

Two of the most exciting novel biologic approaches to the treatment of cancer include the development of oncolytic viruses (see our recent report on this field) and the advancement of cancer vaccines. These approaches as well as the more established field of anticancer therapeutic antibodies (click here for an overview) are driving the next wave of more specific and more effective treatments of cancer. There are currently over twenty phase III cancer vaccine trials ongoing for various indications and new approvals may come as early as 2005. The value of the market for cancer vaccines has the potential to reach $6 billion by 2010 (for a full evaluation see our feature report "Cancer Vaccines"). Cancer vaccines are sub-divided into viral vectors and DNA vaccines; antigen/adjuvant vaccines; whole-cell tumor vaccines; anti-idiotype vaccines; and dendritic cell vaccines.

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 mechanisms that limit dendritic cell immunogenicity. Specifically this group have targeted the suppressor of cytokine signaling-1 (SOCS1) protein.

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 plasmid or viral vectors. In vivo delivery of siRNAs can be carried out by injection into tissues or blood vessels or use of synthetic and viral vectors. At present siRNA technology is predominantly a research tool as exemplified by the present study and it has been estimated that expenditure on siRNA reagents will hit close to $1 billion by 2010. However if a few therapeutically active siRNA products reach the market as disease treatments this market will expand to $3.5 billion (for further information on siRNA see our report "RNAi - technologies, markets and companies"). Using SOCS1 siRNA as a means of increasing the efficacy of dendrite based cancer vaccines is supported by a strong proof of concept. Furthermore since dendritic cell vaccines are most commonly loaded with antigen and matured ex vivo, the therapeutic use of SOCS1 siRNA would also likely be ex vivo thus avoiding potential adverse effects resulting from systemic administration. The further development of SOCS1 siRNA technology is therefore warranted.

As a final point, in June 2004 LeadDiscovery highlighted another study aiming to improve dendritic cell vaccines (click here). One interesting observation made in this earlier study was that increasing tumoral levels of the chemotactic chemokine, CCL20/macrophage inflammatory protein-3alpha (MIP-3alpha) stimulated the movement of endogenous dendritic cells into the tumor core. Thus the co-development of technologies such as those aimed at stimulating dendritic cell maturation (eg SOCS1 siRNA) and technologies that stimulate the homing of the cells into the tumor are likely to produce great strides forwards in the treatment of cancer.

Entry date Sunday, January 23, 2005

Adapted from Shen et al, Nat Biotechnol. 2004 Dec;22(12):1546-53

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