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      Elimination of Metastatic Melanoma Using Gold Nanoshell-Enabled Photothermal Therapy and Adoptive T Cell Transfer

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          Abstract

          Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b +Ly-6G/C + myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control.

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          Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies.

          The Epstein-Barr virus (EBV)-encoded LMP1 protein is expressed in EBV-positive Hodgkin disease and is a potential target for cytotoxic T-lymphocyte (CTL) therapy. However, the LMP1-specific CTL frequency is low, and so far the generation of LMP1-specific CTLs has required T-cell cloning. The toxicity of LMP1 has prevented the use of dendritic cells (DCs) for CTL stimulation, and we reasoned that an inactive, nontoxic LMP1 mutant (DeltaLMP1) could be expressed in DCs and would enable the activation and expansion of polyclonal LMP1-specific CTLs. Recombinant adenoviral vectors expressing LMP1 or DeltaLMP1 were tested for their ability to transduce DCs. LMP1 expression was toxic within 48 hours whereas high levels of DeltaLMP1 expression were achieved with minimal toxicity. DeltaLMP1-expressing DCs were able to reactivate and expand LMP1-specific CTLs from 3 healthy EBV-seropositive donors. LMP1-specific T cells were detected by interferon-gamma (IFN-gamma) enzyme-linked immunospot assay (ELISPOT) assays using the HLA-A2-restricted LMP1 peptide, YLQQNWWTL (YLQ). YLQ-specific T cells were undetectable (less than 0.001%) in donor peripheral blood mononuclear cells (PBMCs); however, after stimulation the frequency increased to 0.5% to 3.8%. Lysis of autologous target cells by CTLs was dependent on the level of LMP1 expression. In contrast, the frequency of YLQ-specific CTLs in EBV-specific CTLs reactivated and expanded using lymphoblastoid cell lines was low and no LMP1-specific cytotoxic activity was observed. Thus, DeltaLMP1 expression in DCs is nontoxic and enables the generation of LMP1-specific CTLs for future adoptive immunotherapy protocols for patients with LMP1-positive malignancies such as EBV-positive Hodgkin disease. Targeting LMP1 in these malignancies may improve the efficacy of current adoptive immunotherapy approaches.
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            IRAK-M removal counteracts dendritic cell vaccine deficits in migration and longevity.

            To function optimally as vaccines, dendritic cells (DCs) must actively migrate to lymphoid organs and maintain a viable, mature state for sufficient time to effectively present their Ag to cognate T cells. Unfortunately, mature DCs rapidly lose viability and function after injection, and only a minority leaves the vaccine site and migrates to lymph nodes. We show that all of these functions can be enhanced in DCs by removal of IL-1R-associated kinase M (IRAK-M). We found that IRAK-M is induced in DCs by TLR ligation and that its absence from these cells leads to increased activation of the p38-MAPK and NF-κB pathways, which, in turn, improves DC migration to lymph nodes, increases their longevity, and augments their secretion of Th1-skewing cytokines and chemokines. These biological effects have immunological consequences. IRAK-M(-/-) DCs increase the proliferation and activation of Ag-specific T cells, and a single vaccination with Ag-pulsed, LPS-matured IRAK-M(-/-) DCs eliminates established tumors and prolongs the survival of EG7 or B16.f10 tumor-bearing mice, without discernible induction of autoimmune disease. Thus, manipulation of IRAK-M levels can increase the potency of DC vaccines by enhancing their Ag-presenting function, migration, and longevity.
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              Author and article information

              Contributors
              Role: Editor
              Journal
              PLoS One
              PLoS ONE
              plos
              plosone
              PLoS ONE
              Public Library of Science (San Francisco, USA )
              1932-6203
              2013
              23 July 2013
              : 8
              : 7
              : e69073
              Affiliations
              [1 ]Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, Texas, United States of America
              [2 ]Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America
              [3 ]Department of Bioengineering, Rice University, Houston, Texas, United States of America
              [4 ]Department of Electrical and Computer Engineering, Rice University, Houston, Texas, United States of America
              [5 ]Bellicum Pharmaceuticals, Houston, Texas, United States of America
              University of Pécs Medical School, Hungary
              Author notes

              Competing Interests: Aaron E. Foster is employed by Bellicum Pharmaceuticals. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

              Conceived and designed the experiments: ASB LCK JKY RAD AEF. Performed the experiments: ASB LCK JKY SKP. Analyzed the data: ASB LCK. Contributed reagents/materials/analysis tools: JKY JPMA AYL PCE. Wrote the paper: ASB LCK JKY RAD AEF.

              ¶ These authors also contributed equally to this work.

              Article
              PONE-D-13-03996
              10.1371/journal.pone.0069073
              3720863
              23935927
              2dd00676-0a70-47d8-935f-7f8957fa1ca6
              Copyright @ 2013

              This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

              History
              : 28 January 2013
              : 5 June 2013
              Page count
              Pages: 13
              Funding
              Studies were supported by the Cancer Prevention Research Institute of Texas grant number RP100189 ( http://www.cprit.state.tx.us), the Norman Hackerman Advanced Research Program ( https://www1.thecb.state.tx.us), and the John Dunn Foundation Collaborative Research Award ( http://johnsdunnfoundation.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
              Categories
              Research Article
              Biology
              Biotechnology
              Bioengineering
              Biomedical Engineering
              Bionanotechnology
              Immunology
              Immunity
              Immune Activation
              Immunotherapy
              Immunologic Subspecialties
              Tumor Immunology
              Medicine
              Oncology
              Basic Cancer Research
              Metastasis
              Cancer Treatment
              Immunotherapy

              Uncategorized
              Uncategorized

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