Ferent donors. doi:10.1371/journal.pone.Tubastatin-A site 0051805.g19 and U373 cell lines constitutively express high levels of surface NKD2D ligands ULBP-2 and ULBP-3 (data not shown) as well as MIC-A for U373, suggesting that the additive effect of TMZ on cd T cell-based cytotoxicity may be partially mediated by nonpeptide ligands [51]. Besides inducing tumor associated stress molecules, chemotherapy can also augment immunotherapy in several ways, such as by enhancing the persistence of tumor reactive T lymphocytes and by increasing tumor trafficking of tumor responsive T cells, and by modulating immunosuppressive factors [52]. Thus administration of chemotherapy prior to cellular immunotherapy can modulate an immune environment that can be beneficial to the infused immune effector cells, such as cd T cells. It has been shown that chemotherapy treatments can facilitate the rapid infiltration of large numbers of cd T cells into tumors and prior to invasion of Tc1 cells [53]. Furthermore,temozolomide based chemotherapy has been shown to decrease the population of Fox-P3+ regulatory T cells, which provides an environment to further enhance the immune response [54]. Therefore, rapidly emerging evidence supports the crucial contribution of the innate immune system to the anti-tumorigenicity of conventional chemotherapy-based cancer treatments [22,26,49]. In the context of GBM therapy, in order to access the chemotherapy derived window of opportunity of tumor vulnerability it may be beneficial to place a high concentration of cd T cells at the tumor site and to protect these effector cells, by gene transfer of MGMT, from the cytotoxic effects of TMZ chemotherapy, which would otherwise reduce or abrogate their function. In the present study, we successfully demonstrated two key aspects that are essential to the success of such a localized and a passive immunotherapy approach to target GBM: i) the genetic engineer-Drug Resistant cd T Cell Immunotherapying of cd T cells and their expansion to concentrations sufficient for a therapeutic dose based on previous studies of cd T cell therapy of human xenografts in immunodeficient mice [35], and ii) the retention of anti-tumor cytotoxicity of the genetically engineered cells at concentrations of temozolomide that upregulate tumor associated stress molecules that activate effector cell functions. Intra-cavity post-resection administration of gliomareactive genetically engineered cd T cells presents one of the few opportunities to deliver concentrated cellular immunotherapy directly to the site of residual malignancy at the time of maximal tumor vulnerability during high dose chemotherapy. The in vitro effectiveness of our cd T cell-based DRI strategy provides thenecessary foundation to pursue such an innovative approach to the treatment of high-grade gliomas.AcknowledgmentsWe would like to thank Arthur Nienhuis (St. Jude University, Memphis, TN) for the SIV vector system.Author ContributionsConceived and designed the experiments: LSL GYG HTS. Performed the experiments: JB AD YS AJ. Analyzed the data: LSL AD HTS. Contributed reagents/materials/analysis tools: LSL GYG HTS. Wrote the paper: LSL AD HTS.
Psoriasis is a chronic immune-mediated skin disorder with frequent clinical relapse [1]. The majority of patients with moderate-to-severe psoriasis require specific topical and systemic therapies including phototherapy (psoralen ultraviolet A therapy (PUVA) or narrow-band ultraviolet B (NB-UVB)), Oltipraz methotrexate [2], cyclospor.Ferent donors. doi:10.1371/journal.pone.0051805.g19 and U373 cell lines constitutively express high levels of surface NKD2D ligands ULBP-2 and ULBP-3 (data not shown) as well as MIC-A for U373, suggesting that the additive effect of TMZ on cd T cell-based cytotoxicity may be partially mediated by nonpeptide ligands [51]. Besides inducing tumor associated stress molecules, chemotherapy can also augment immunotherapy in several ways, such as by enhancing the persistence of tumor reactive T lymphocytes and by increasing tumor trafficking of tumor responsive T cells, and by modulating immunosuppressive factors [52]. Thus administration of chemotherapy prior to cellular immunotherapy can modulate an immune environment that can be beneficial to the infused immune effector cells, such as cd T cells. It has been shown that chemotherapy treatments can facilitate the rapid infiltration of large numbers of cd T cells into tumors and prior to invasion of Tc1 cells [53]. Furthermore,temozolomide based chemotherapy has been shown to decrease the population of Fox-P3+ regulatory T cells, which provides an environment to further enhance the immune response [54]. Therefore, rapidly emerging evidence supports the crucial contribution of the innate immune system to the anti-tumorigenicity of conventional chemotherapy-based cancer treatments [22,26,49]. In the context of GBM therapy, in order to access the chemotherapy derived window of opportunity of tumor vulnerability it may be beneficial to place a high concentration of cd T cells at the tumor site and to protect these effector cells, by gene transfer of MGMT, from the cytotoxic effects of TMZ chemotherapy, which would otherwise reduce or abrogate their function. In the present study, we successfully demonstrated two key aspects that are essential to the success of such a localized and a passive immunotherapy approach to target GBM: i) the genetic engineer-Drug Resistant cd T Cell Immunotherapying of cd T cells and their expansion to concentrations sufficient for a therapeutic dose based on previous studies of cd T cell therapy of human xenografts in immunodeficient mice [35], and ii) the retention of anti-tumor cytotoxicity of the genetically engineered cells at concentrations of temozolomide that upregulate tumor associated stress molecules that activate effector cell functions. Intra-cavity post-resection administration of gliomareactive genetically engineered cd T cells presents one of the few opportunities to deliver concentrated cellular immunotherapy directly to the site of residual malignancy at the time of maximal tumor vulnerability during high dose chemotherapy. The in vitro effectiveness of our cd T cell-based DRI strategy provides thenecessary foundation to pursue such an innovative approach to the treatment of high-grade gliomas.AcknowledgmentsWe would like to thank Arthur Nienhuis (St. Jude University, Memphis, TN) for the SIV vector system.Author ContributionsConceived and designed the experiments: LSL GYG HTS. Performed the experiments: JB AD YS AJ. Analyzed the data: LSL AD HTS. Contributed reagents/materials/analysis tools: LSL GYG HTS. Wrote the paper: LSL AD HTS.
Psoriasis is a chronic immune-mediated skin disorder with frequent clinical relapse [1]. The majority of patients with moderate-to-severe psoriasis require specific topical and systemic therapies including phototherapy (psoralen ultraviolet A therapy (PUVA) or narrow-band ultraviolet B (NB-UVB)), methotrexate [2], cyclospor.
