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      Overcoming tumor immune evasion with an unique arbovirus

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          Abstract

          Combining dendritic cell vaccination with the adjuvant effect of a strain of dengue virus may be a way to overcome known tumor immune evasion mechanisms. Dengue is unique among viruses as primary infections carry lower mortality than the common cold, but secondary infections carry significant risk of hypovolemic shock. While current immuno-therapies rely on a single axis of attack, this approach combines physiological (hyperthermic reduction of tumor perfusion), immunological (activation of effector cells of the adaptive and innate immune system), and apoptosis-inducing pathways (sTRAIL) to destroy tumor cells. The premise of using multiple mechanisms of action in synergy with a decline in the ability of the tumor cells to employ resistance methods suggests the potential of this combination approach in cancer immunotherapy.

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          Cancer immunotherapy: moving beyond current vaccines.

          Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.
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            The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas.

            In 1891, William B. Coley injected streptococcal organisms into a patient with inoperable cancer. He thought that the infection he produced would have the side effect of shrinking the malignant tumor. He was successful, and this was one of the first examples of immunotherapy. Over the next forty years, as head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. These products became known as Coley's Toxins. He and other doctors who used them reported excellent results, especially in bone and soft-tissue sarcomas. Despite his reported good results, Coley's Toxins came under a great deal of criticism because many doctors did not believe his results. This criticism, along with the development of radiation therapy and chemotherapy, caused Coley's Toxins to gradually disappear from use. However, the modern science of immunology has shown that Coley's principles were correct and that some cancers are sensitive to an enhanced immune system. Because research is very active in this field, William B. Coley, a bone sarcoma surgeon, deserves the title "Father of Immunotherapy".
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              Tumor Regression and Autoimmunity after Reversal of a Functionally Tolerant State of Self-reactive CD8+ T Cells

              Many tumor-associated antigens are derived from nonmutated “self” proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I–restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.
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                Author and article information

                Contributors
                bruce.lyday@primevax.com
                tony.chen@primevax.com
                skesari@ucsd.edu
                bminev@ucsd.edu
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                16 January 2015
                16 January 2015
                2015
                : 13
                : 1
                : 3
                Affiliations
                [ ]PrimeVax, LLC, Garden Grove, USA
                [ ]Department of Neurosciences, Translational Neuro-Oncology Laboratories, UC San Diego, La Jolla, CA 92093 USA
                [ ]Moores UCSD Cancer Center, UC San Diego, La Jolla, CA 92093 USA
                [ ]Division of Neurosurgery, UC San Diego, La Jolla, CA 92093 USA
                [ ]Genelux Corporation, San Diego Science Center, San Diego, CA 92109 USA
                Article
                349
                10.1186/s12967-014-0349-0
                4307212
                25592450
                02ecf071-125e-44ff-83b7-40cff64ddc1c
                © Lyday et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 September 2014
                : 1 December 2014
                Categories
                Review
                Custom metadata
                © The Author(s) 2015

                Medicine
                death receptors,dendritic cell,dengue fever,hyperthermia,immunotherapy,immune evasion,spontaneous regression,soluble trail

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