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New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
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Advanced Drug Delivery Reviews (v.58, #8)
Challenges for cancer vaccine development by Z. Tabi; S. Man (pp. 902-915).
The first generation of human cancer vaccines has been tested in phase III clinical trials, but only a few of these have demonstrated sufficient efficacy to be licensed for clinical use. This article reviews some of the mechanisms that could contribute to these limited clinical responses, and highlights the challenges faced for development of future vaccines.
Keywords: Immunotherapy; Immune evasion; Tumour vaccines
Improved peptide vaccine strategies, creating synthetic artificial infections to maximize immune efficacy by Sjoerd H. van der Burg; Martijn S. Bijker; Marij J.P. Welters; R. Offringa; Cornelis J.M. Melief (pp. 916-930).
Soon after it was realized that T-cells recognize their target antigens as small protein fragments or peptides presented by MHC molecules at the cell surface, these peptide epitopes have been tried as vaccines. Human testing of such vaccines, although protective in mouse models, has produced mixed results. Since these initial trials, there has been an tremendous increase in our understanding of how infectious organisms can induce potent immune responses. In this article we review the key changes in the design, formulation and delivery of synthetic peptide vaccines that are applied to improve peptide vaccine strategies.
Keywords: Peptides; Cell-mediated immunity; Adjuvants; Immunotherapy; Tumour antigens
Recombinant viral vectors: Cancer vaccines by Richard Harrop; Justin John; Miles W. Carroll (pp. 931-947).
To date cancer vaccines have yet to show efficacy in a phase III trial. However, the clinical benefit seen with monoclonal antibody mediated therapies (e.g., Herceptin) has provided proof of principle that immune responses directed against tumour-associated antigens could have therapeutic potential. The failure of past cancer vaccine trials is likely due to several factors including the inappropriate choice of tumour antigen, use of an unoptimised antigen delivery system or vaccination schedule or selection of the wrong patient group. Any one of these variables could potentially result in the induction of an immune response of insufficient magnitude to deliver clinical benefit. Live recombinant viral vaccines have been used in the development of cancer immunotherapy approaches for the past 10 years. Though such vectors are self-adjuvanted and offer the ability to express multiple tumour-associated antigens (TAAs) along with an array of immune co-factors, arguably, they have yet to demonstrate convincing efficacy in pivotal clinical trials. However, in recent years, more coordinated studies have revealed mechanisms to optimise current vectors and have lead to the development of new advantageous vector systems. In this review, we highlight that live recombinant viral vectors provide a versatile and effective antigen delivery system and describe the optimal properties of an effective viral vector. Additionally, we discuss the advantages and disadvantages of the panel of recombinant viral systems currently available to cancer vaccinologists and how they can work in synergy in heterologous prime boost protocols and with other treatment modalities.
Keywords: Viral vector; Tumour antigen; Immune response; Manufacture; Cancer immunotherapy; Clinical experience
Regulating the immune response to tumours by Gareth J. Betts; Sarah L. Clarke; Hannah E. Richards; Andrew J. Godkin; Awen M. Gallimore (pp. 948-961).
Naturally occurring regulatory T cells (Tregs) have been shown to suppress immune responses to self-antigens, thereby limiting autoimmunity. In the case of tumours, where immune responses to self-antigens are beneficial and lead to elimination of the tumour, such suppressive activity is actually detrimental to the host. Manipulation of Tregs holds great promise for the immunotherapy of cancer. Several studies performed using rodent models and indicate that Tregs cells inhibit effective anti-tumour immune responses and that their removal promotes tumour rejection. The increasing number of studies of Tregs in patients with cancer also point to a role for these cells in promoting disease progression. This review summarises the findings of these studies and addresses the advantages and potential pitfalls of manipulating Treg activity for the treatment of cancer.
Keywords: Tumour immunity; T regulatory cells
The chemokine network: A target in cancer biology? by Violet I.F. Slettenaar; Julia L. Wilson (pp. 962-974).
Chemokine gradients are central to the movement of cells in both homeostatic and pathological processes. Most cancers express a complex array of chemokines that influence the local microenvironment through recruitment of stromal cells and by stimulating angiogenesis. Recently, the discovery of chemokine receptors on tumor cells has led to speculation that the chemokine system may be involved in cancer cell growth and survival, and possibly the development of site-specific spread. Understanding the networks of chemokines and their receptors in cancer will enable manipulation of this system. Both chemokines and their receptors represent targets for therapeutic intervention either with antibodies or small molecule antagonists. However, due to the complexity of the system, and the number of chemokines and receptors that are also expressed by normal cells, issues remain concerning whether systemic or local drug delivery are preferable and whether the redundancy of the system will compensate if one chemokine or receptor is targeted. Nevertheless, efficacy has been demonstrated in a number of experimental models. By targeting this network, it may be possible to generate anti-tumor immune responses by altering the chemokine and/or leukocyte balance in tumors; alternatively, chemokine/chemokine receptor-expressing cancer cells could be directly targeted.
Keywords: Chemokine; Cancer; Tumor cell
Combined chemoimmunotherapy of solid tumours: Improving vaccines? by Anna K. Nowak; Richard A. Lake; Bruce W.S. Robinson (pp. 975-990).
Cytotoxic chemotherapy not only affects the tumour but also targets dividing lymphocytes, the very cells required to develop an immune response. Hence, chemo- and immunotherapy have been seen as antagonistic. It is now clear that the way a chemotherapeutic drug kills a tumour cell determines how that dying cell interacts with the immune system and whether the interaction leads to an immune response. Chemotherapy also depletes regulatory T cells, potentially enhancing immune responses. Furthermore, lymphodepletion triggers homeostatic T cell reconstitution, creating new populations of pre-T cells that need education in the thymic environment. Post-chemotherapy immune system reconstitution may provide a unique opportunity for therapeutic intervention by shaping the repertoire towards reactivity to tumour antigens. An understanding of the underlying cellular and immunological events in both animal models and patients undergoing chemotherapy will guide decisions about which immunomodulatory approaches may be effective with different cytostatic drugs and hence to develop appropriate scheduling for integration of the treatment modalities.
Keywords: Immunotherapy; Antineoplastic agents; Tumour vaccines; Tumour antigen; Chemoimmunotherapy