Other Possible Cell Types

There are several other cell types that could be used to facilitate cytokine mediated gene therapy for GU tumors. Peripheral blood can be used not only as a source of macrophage and DC precursors but also to isolate biologically active T-cells. Over a decade ago several reports suggested that autologous T-cells could be activated in vitro with cytokines and used to treat prostate or renal cancer (122-124). Tumor infiltrating T-lymphocytes isolated and treated with cytokines have also been utilized for prostate, bladder, and renal cancer (125). The myriad strategies for isolation, enrichment, expansion, and possible engineering of T-cells for adoptive therapy have recently been reviewed (126). In an attempt to target adoptive T-cell therapy to prostate cancer, human T-cells that were engineered to express a chimeric receptor for the tumor marker erbB2 demonstrated therapeutic potential in a xenograft models (127). In another study, four of five prostate cancer patients T-cells were isolated and modified to express a receptor that recognized the PSMA lysed prostate cancer cells and expressed cytokines in response to binding to PSMA (94). Attempts to isolate and propagate tumor antigen reactive T-cell clones for therapeutic use have been ongoing. Until recently, minimal success was reported but newer patient lymphodepletion conditioning protocols yielded objective clinical responses (128). We are currently evaluating a model for adoptive cell therapy using in situ cytokine gene therapy to induce tumor reactive T-cells that can be isolated from splenocytes and subsequently transferred to naïve animals where they confer resistance to tumor challenge (129). Cytokine induced killer cells isolated from the peripheral blood of patients with metastatic renal cancer and transduced with the IL-2 gene have been shown to be safe when reinjected into patients and can generate immune activities (130).

Another potential cell population that holds great potential are bone marrow derived stem cells. We have developed a novel anti-bone metastasis therapy using bone marrow stem cells to transport an active IL-12 gene to the bone (131). In these preliminary experiments we have used a retroviral vector, DFG-mIL12, which showed previously to efficiently transduce and mediate the expression of p35 and p40 at high levels (132). DFG-eGFP, which has an identical retroviral backbone and has been shown to efficiently transduce eGFP (visualized in living and fixed tissues) served as control vector (132). The distinct advantage of retroviral vectors relative to other viral vectors is their ability to stably integrate a therapeutic gene into the host cell DNA without expressing immunogenic viral proteins. Retroviral vectors may, therefore, be useful for ex vivo gene therapy applications such as production of autologous or allogeneic cancer cells as vaccines (86,100). Retroviral

Fig. 1. In situ and systemic cytokine gene modified APC, cytokine gene modified vaccines, and cytokine modified bone marrow stem cell targeting for prostate cancer therapy.

vectors however, have several disadvantages with regard to clinical use. In general they only infect dividing cells, have poor cell penetration, and diffuse poorly across cells at the injection site. Retroviral vectors require specialized packaging cells which yield relatively low titers. Retroviral vectors also have a relatively small genome, limiting their carrying capacity for engineered genes. Because retroviruses randomly insert their DNA into the cell genome, they have mutagenic potential with concerns that this may cause a malignancy as in two children in gene replacement trials (133).

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