Dataset Information

Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival.

ABSTRACT: Lung cancer is a leading cause of cancer death due to the high incidence of metastasis; therefore, novel and effective treatments are urgently needed. A current strategy is cancer-specific targeted gene therapy. Although many identified that cancer-specific promoters are highly specific, they tend to have low activity compared with the ubiquitous cytomegalovirus (CMV) promoter, limiting their application. We developed a targeted gene therapy expression system for lung cancer that is highly specific with strong activity. Our expression vector uses the survivin promoter, highly expressed in many cancers but not normal adult tissues. We enhanced the survivin promoter activity comparable to the CMV promoter in lung cancer cell lines using an established platform technology, whereas the survivin promoter remained weak in normal cells. In mouse models, the transgene was specifically expressed in the lung tumor tissue, compared with the CMV promoter that was expressed in both normal and tumor tissues. In addition, the therapeutic gene BikDD, a mutant form of pro-apoptotic Bcl2 interacting killer, induced cell killing in vitro, and inhibited cell growth and prolonged mouse survival in vivo. Importantly, there was virtually no toxicity when BikDD was expressed with our expression system. Thus, the current report provides a therapeutic efficacy and safe strategy worthy of development in clinical trials treating lung cancer.

SUBMITTER: Sher YP

PROVIDER: S-EPMC2763377 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival.

Sher Y-P YP Tzeng T-F TF Kan S-F SF Hsu J J Xie X X Han Z Z Lin W-C WC Li L-Y LY Hung M-C MC

Oncogene 20090713 37

Lung cancer is a leading cause of cancer death due to the high incidence of metastasis; therefore, novel and effective treatments are urgently needed. A current strategy is cancer-specific targeted gene therapy. Although many identified that cancer-specific promoters are highly specific, they tend to have low activity compared with the ubiquitous cytomegalovirus (CMV) promoter, limiting their application. We developed a targeted gene therapy expression system for lung cancer that is highly speci ...[more]

PMID: 19597463

Similar Datasets

Project description:BACKGROUND:Mismatch Repair Deficiency (MMR-D)-related tumors are highly immunogenic and constitute ideal vaccination targets. In a proof-of-concept study delayed tumorigenesis and prolonged survival has been shown in a clinically-relevant mouse model for MMR-D-related diseases (=MLH1 knock out mice). To refine this approach, vaccination was combined with immune modulatory low-dose chemotherapy to polarize immune regulatory subtypes. METHODS:Mice (prophylactic: 8-10?weeks; therapeutic: >?36?weeks) received a single injection of cyclophosphamide (CPX, 120?mg/kg bw, i.p.) or gemcitabine (GEM, 100?mg/kg bw, i.p.) prior to vaccination (lysate of a gastrointestinal tumor allograft, 10?mg/kg bw, n?=?9 mice/group). The vaccine was given repetitively (10?mg/kg bw, s.c., 4 x / once a week, followed by monthly boosts) until tumor formation or progression. Tumor growth ([18F] FDG PET/CT imaging) and immune responses were monitored (flow cytometry, IFN? ELISpot). The microenvironment was analyzed by immunofluorescence. RESULTS:Prophylactic application of GEM + lysate delayed tumorigenesis compared to lysate monotherapy and CPX-pre-treatment (median time of onset: 53 vs. 47 vs. 48?weeks). 33% of mice even remained tumor-free until the experimental endpoint (= 65?weeks). This was accompanied by long-term effect on cytokine plasma levels; splenic myeloid derived suppressor cells (MDSC) as well as regulatory T cell numbers. Assessment of tumor microenvironment from GEM + lysate treated mice revealed low numbers of MDSCs, but enhanced T cell infiltration, in some cases co-expressing PD-L1. Therapeutic chemo-immunotherapy (GEM + lysate) had minor impact on overall survival (median time: 12 (GEM + lysate) vs. 11.5 (lysate) vs. 3?weeks (control)), but induced complete remission in one case. Dendritic and T cell infiltrates increased in both treatment groups. Reactive T cells specifically recognized MLH1-/- tumor cells in IFN? ELISpot, but lacked response towards NK cell targets YAC-1. CONCLUSIONS:Combined chemo-immunotherapy impairs tumor onset and growth likely attributable to modulation of immune responses. Depleting or 're-educating' immunosuppressive cell types, such as MDSC, may help moving a step closer to combat cancer.

Project description:Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m2/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-?] and 41.1 months (95% CI, 21.6-?), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR.

Project description:Hepatic metastases are diagnosed synchronously in 3-14% of patients with gastric cancer, and metachronously in up to 37% of patients following ''curative" gastrectomy. Most patients who have gastric cancer and hepatic metastasis are traditionally treated with palliative chemotherapy. The impact of liver resection is still controversial. We attempted to assess whether liver resection can improve survival in cases of metachronous hepatic metastases from gastric cancer through a nationwide database.We conducted a nationwide cohort study using a claims dataset from Taiwan's National Health Insurance Research Database (NHIRD). We identified all patients with gastric cancer (diagnostic code ICD-9: 151.x) from the Registry for Catastrophic Illness Patient Database (RCIPD) of the NHIRD who received gastrectomy and as well as those with metachronous (≥180 days after gastrectomy) liver metastases (ICD-9 code: 197.7) between 1996/01/01 and 2012/12/31. Patients with other malignancies, with metastasis in the initial admission for gastrectomy and with other metastases were excluded. They were divided into two groups, liver resection group and non-resection group. All patients were followed till 2013/12/31 or withdrawn from the database because of death.653 patients who fullfilled the inclusion criteria were included in the research. They were divided into liver resection group (34 patients) and non-resection group (619 patients). There were no differences between the two groups in gender, Charlson Comorbidity index and major coexisting disease. Kaplan-Meier analysis demostrated the liver resection group had significantly better overall survival than the non-resection group. (1YOS: 73.5% vs. 19.7%, 3YOS: 36.9% vs. 6.6%, 5YOS: 24.5.3% vs. 4.4%, p <0.001). After COX analysis, the liver resection group showed statistical significance for improved patient survival (HR = 0.377, 95%CI: 0.255-0.556. p<0.001).Liver resection in patients presenting with metachronous hepatic metastases as the sole metastases after curative resection of gastric cancer is associated with a significant survival improvement and should be considered a treatment option for such patients.

Project description:BACKGROUND:Lung transplantation is a life-saving surgical replacement of diseased lungs in patients with end-stage respiratory malfunctions. Despite remarkable short-term recovery, long-term lung survival continues to face several major challenges, including chronic rejection and severe toxic side effects due to global immunosuppression. Stem cell-based immunotherapy has been recognized as a crucial immunoregulatory regimen in various preclinical and clinical studies. Despite initial therapeutic outcomes, conventional stem cells face key limitations. The novel Cymerus™ manufacturing facilitates production of a virtually limitless supply of consistent human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells, which could play a key role in selective immunosuppression and graft repair during rejection. METHODS:Here, we demonstrated the impact of iPSC-derived human MSCs on the development of immune tolerance and long-term graft survival in mouse orthotopic airway allografts. BALB/c???C57BL/6 allografts were reconstituted with iPSC-derived MSCs (2 million/transplant/at d0), and allografts were examined for regulatory T cells (Tregs), oxygenation, microvascular blood flow, airway epithelium, and collagen deposition during rejection. RESULTS:We demonstrated that iPSC-derived MSC treatment leads to significant increases in hTSG-6 protein, followed by an upregulation of mouse Tregs and IL-5, IL-10, and IL-15 cytokines, which augments graft microvascular blood flow and oxygenation, and thereby maintained a healthy airway epithelium and prevented the subepithelial deposition of collagen at d90 post transplantation. CONCLUSIONS:Collectively, these data confirmed that iPSC-derived MSC-mediated immunosuppression has potential to establish immune tolerance and rescue allograft from sustained hypoxic/ischemic phase, and subsequently limits long-term airway epithelial injury and collagen progression, which therapeutically warrant a study of Cymerus iPSC-derived MSCs as a potential management option for immunosuppression in transplant recipients.

Dataset Information

Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival.

Publications

Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure