Purpose: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for highrisk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease.Experimental Design: Patients with invasive bladder cancer scheduled for cystectomy or patients with T a tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored.Results: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-γ increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells.Conclusions: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies. Clin Cancer Res; 16(12); 3279-87. ©2010 AACR.
Summary Interleukin‐2 (IL‐2) is one of the most studied cytokines driving T‐cell proliferation, activation and survival. It binds to the IL‐2 receptor consisting of three chains, the α (CD25), β and common γ (γc). The binding of the CD25 chain to IL‐2 is necessary to expose high‐affinity binding sites for the β and γc chains, which, in turn, are responsible for downstream signalling. A high level of soluble CD25 (sCD25) has been associated with a poor prognosis in patients with non‐Hodgkin’s lymphoma. The function and source of origin of this soluble receptor is not well investigated. In the present study we hypothesized that T regulatory (Treg) cells may release CD25 to act as a decoy receptor for IL‐2, thereby depriving T‐effector cells of IL‐2. Peripheral blood from patients with B‐cell malignancies (n = 26) and healthy controls (n = 27) was investigated for the presence and function of FoxP3+ Treg cells and sCD25 by multi‐colour flow cytometry and enzyme‐linked immunosorbent assay. Further, the proliferative capacity of T cells was evaluated with or without the presence of recombinant sCD25. The results demonstrate that Treg cells from patients had lower CD25 expression intensity and that they released CD25 in vitro. Further, high levels of Treg cells correlated with sCD25 plasma concentration. Recombinant sCD25 could suppress T‐cell proliferation in vitro. In conclusion, the release of sCD25 by Treg cells may be a mechanism to deprive IL‐2 and thereby inhibit anti‐tumour T‐cell responses.
Summary Cytotoxic CD4+ T cells have been found in patients with chronic lymphocytic leukaemia (CLL) and seem to be involved in the regulation of malignant B cells. The CD4+ T regulatory cells (Tregs) can regulate various immune cells, including B cells, by inducing their apoptosis. Hence, different subgroups of CD4+ T cells may be involved in the regulation of malignant B cells. In this study, the cytotoxic phenotype and function of various CD4+ T‐cell subgroups were investigated in patients with B‐cell malignancies. Peripheral blood was collected from patients with CLL, various B‐cell lymphomas, healthy adult donors, children with precursor B‐cell acute lymphoblastic leukaemia (pre‐B ALL) and from healthy children. CD4+ T cells (CD3+ CD4+ FoxP3−), Tregs (CD3+ CD4+ CD127low FoxP3+) and CD127high FoxP3+ T cells (CD3+ CD4+ CD127high FoxP3+) were analysed for their expression of the cytolytic markers CD107a and Fas ligand. Patients with CLL had increased CD107a expression on all tested T‐cell subgroups compared with healthy donors. Similar results were found in patients with B‐cell lymphomas whereas the CD107a expression in children with pre‐B ALL was no different from that in healthy controls. Fas ligand expression was similar between patient cells and cells of healthy donors. CD4+ T cells and Tregs from patients with CLL and healthy donors were subsequently purified and cultured in vitro with autologous B cells. Both subgroups lysed B cells and killing was confirmed by granzyme ELISAs. In conclusion, cytotoxic populations of CD4+ T cells, including Tregs, are present in patients with B‐cell malignancy and may be an important factor in immune‐related disease control.
CD40, a tumor necrosis factor receptor family member, is an emerging target for cancer therapy being best appreciated as an important regulator of the anti-tumor immune response. In this study, we report the development of a replication-defective recombinant adenovirus (RAd) vector expressing human CD40 ligand (RAd-hCD40L) and show that sustained engagement of the CD40 pathway in malignant cells results in direct anti-proliferative and pro-apoptotic effects. Thus, transduction of CD40-positive bladder, cervical and ovarian carcinoma cell lines with RAd-hCD40L potently inhibits their proliferation in vitro, whereas CD40-negative lines remain unresponsive. RAd-hCD40L is also found to be superior to recombinant CD40L in inducing carcinoma cell death and in amplifying the cytotoxic effects of the chemotherapeutic agents 5-fluorouracil, cis-platin and mitomycin C. Soluble CD40L is produced by RAd-hCD40L transduced carcinoma cells but unlike other soluble tumor necrosis factor family ligands, it does not interfere with the death-promoting activity of its membrane-bound form. In a mouse xenograft tumor model bearing a human bladder carcinoma, intratumoral delivery of RAd-hCD40L suppresses cancer growth. These findings highlight the potential of exploiting the CD40 pathway in carcinomas using CD40L gene transfer alone or in combination with other modalities for cancer therapy. Our results have also broader implications in understanding the multifaceted anti-tumor activities of the CD40 pathway in carcinomas, which thus offer an attractive option for future clinical application.
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