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dc.contributorNot Applicableen_US
dc.contributor.authorEGILMEZ, NEJAT K Principal Investigatoren_US
dc.date30-Apr-15en_US
dc.date2010en_US
dc.date.accessioned2011-04-18T21:05:18Zen_US
dc.date.accessioned2011-04-19T18:31:25Z
dc.date.available1-Apr-03en_US
dc.date.available2011-04-18T21:05:18Zen_US
dc.date.available2011-04-19T18:31:25Z
dc.date.issued2011-04-18T21:05:18Zen_US
dc.identifier7986830en_US
dc.identifier2R01CA100656-07A1en_US
dc.identifier100656en_US
dc.identifier.urihttp://hdl.handle.net/10477/1102
dc.descriptionadaptive immunity;Back;base;cancer therapy;CD8B1 gene;Cell physiology;Cells;Chronic;clinical efficacy;clinically relevant;Complex;controlled release;cytokine;Dendritic Cells;Development;Disease;Drug Formulations;Effector Cell;Event;Funding;Goals;Gold;Granulocyte-Macrophage Colony-Stimulating Factor;IFN consensus sequence binding protein;IL2RA gene;Immune;immunogenic;Immunotherapy;improved;in vivo;inhibitor/antagonist;Interferons;Interleukin-12;Local Therapy;lymph nodes;macromolecule;Mediating;Memory;Modeling;Molecular;Molecular Analysis;Monitor;Mus;Myelogenous;nanorod;Natural immunosuppression;Natural Killer Cells;Neoplasm Metastasis;novel;Operative Surgical Procedures;paracrine;Pathway interactions;Pharmaceutical Preparations;Phenotype;Population;Primary Neoplasm;programs;public health relevance;Recombinant Cytokines;Recombinant Proteins;Recruitment Activity;Regulation;Regulatory Pathway;Research;Research Design;Resectable;response;Role;Small Interfering RNA;small molecule;Suppressor-Effector T-Lymphocytes;T-Lymphocyte;Technology;Testing;Treatment Efficacy;tumor;tumor eradication;tumor progression;Work;en_US
dc.descriptionAmount: $ 323112en_US
dc.description.abstractDESCRIPTION (provided by applicant): Sustained delivery of Interleukin-12 and GM-CSF to the tumor microenvironment induces rapid activation of pre-existing CD8+ Teffector/memory cells, promotes elimination of CD4+ CD25+ Foxp3+ T-suppressor cells and results in the priming of a secondary CD8+ T-effector response in the tumor-draining lymph nodes (TDLN). However, reversal of tumor immune suppression is transient and effector activation is followed by a dramatic rebound of T-suppressor cells and return of T-effector quiescence. Re-stimulation results in the intensification of the regulatory rebound and ultimately, in the loss of therapeutic efficacy. Recent work demonstrated that both CD8+ T-effector cell priming and T-suppressor cell rebound were mediated by the same myeloid Dendritic cell (DC) population that was recruited to the TDLN following treatment. More importantly, IFN? was required for the development of both the initial immunogenic and the subsequent tolerogenic DC (tDC) phenotype. The broad hypothesis that will be tested in this application is that IFN?-driven immunogenic and tolerogenic pathways in DC can be uncoupled and that selective inhibition of the tolerogenic pathway will neutralize the homeostatic T-suppressor cell rebound, resulting in durable tumor regression. To this end, Aim 1 studies are designed to delineate the little-known mechanisms controlling the IFN?-driven differentiation of immunogenic DC (iDC) to tDC. More specifically, the specific roles of selected interferon regulatory factors (IRFs) in the differentiation of iDC and tDC phenotypes are elucidated to identify potential checkpoints that can be targeted for selective blocking of tDC development and persistence. In Aim 2, two different strategies aimed at abrogating counter-regulation via the use of unique in vivo macromolecule delivery technologies are tested. First, potential regulators of post-therapy tDC differentiation and activity, including IRF-8, SOCS-1, IDO-1/2, GCN-2 and MyD88 as well as additional candidates that are identified in Aim 1, are targeted via siRNA/gold nanorod complexes and sustained-release cytokine/small molecule drug formulations to block tDC function. Second, based on recent findings demonstrating considerable plasticity in T-suppressor cell phenotype, the above technologies are utilized to re-program rebounding T-suppressor cells via Foxp3 silencing and delivery of TH1/TH17-promoting cytokines. In Aim 3, the long-term curative potential of the above approach is investigated in two clinically-relevant tumor models. First, a surgical metastasis model is utilized to determine whether local abrogation of the T-suppressor cell rebound will result in enhanced eradication of disseminated disease. In the second model, the utility of chronic immune therapy in long-term management of non- resectable disease is evaluated in an advanced primary tumor model. Elucidation of the molecular basis of treatment-induced homeostatic counter-regulation and identification of potential regulatory checkpoints that can be targeted for neutralization of the T-suppressor rebound represents a new paradigm, which if successful, can significantly improve clinical efficacy of immune-based therapies. PUBLIC HEALTH RELEVANCE: This proposal will define the molecular mechanisms underlying the homeostatic regulatory rebound that short-circuits therapy-induced antitumor cytotoxic cell activity. Delineation of how treatment itself leads to the mobilization of a regulatory counter-response is expected to reveal checkpoints that can be targeted for abrogation of the regulatory rebound. To this end, novel controlled-release formulations of siRNA, recombinant proteins and small molecule drugs are utilized in conjunction with therapy to target anticipated checkpoints and reprogram regulatory cells to achieve durable tumor regression.en_US
dc.titleINTEGRATING INNATE AND ADAPTIVE IMMUNITY IN CANCER THERAPYen_US
dc.typeNIH Grant Awarden_US


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