There is a critical need to develop new and effective cancer therapies that target bone, the primary metastatic site for prostate cancer and other malignancies. Among the various therapeutic approaches being considered for this application, gene-modified cell-based therapies may have specific advantages. Gene-modified cell therapy uses gene transfer and cell-based technologies in a complementary fashion to chaperone appropriate gene expression cassettes to active sites of tumor growth. In this paper, we briefly review potential cell vehicles for this approach and discuss relevant gene therapy strategies for prostate cancer. We further discuss selected studies that led to the conceptual development and preclinical testing of IL-12 gene-modified bone marrow cell therapy for prostate cancer. Finally, we discuss future directions in the development of gene-modified cell therapy for metastatic prostate cancer, including the need to identify and test novel therapeutic genes such as GLIPR1.
With an estimated 27 050 deaths in 2007, prostate cancer is the most common cancer and a leading cause of cancer death in men.1 Although prostate cancer deaths have declined among white and African-American men since the early 1990s, mortality rates remain unacceptably high. Standard therapy for localized disease involves radical prostatectomy or radiation therapy, both of which are often associated with significant morbidity.2 In many patients, microscopic metastases are present at the time of diagnosis of the primary disease, and these patients often experience progressive disease following localized therapy.3 Currently, the only established treatment for metastatic prostate cancer is palliative hormone therapy.4 Although metastatic prostate cancer is a multifocal disease, the primary metastatic site for prostate cancer is bone. Cytotoxic chemotherapeutics are currently being used in various approaches to treat prostate cancer bone metastasis with limited success.5 Therefore, there is a critical need to develop new therapeutic approaches, including gene- and cell-based therapies that can be administered systemically and target bone metastases.
Three general categories of cancer gene therapy have emerged. Gene replacement involves the transfer of functional transcriptionally active gene cassettes that substitute for damaged or nonfunctional antitumor genes, for example, tumor suppressors. Oncolytic virotherapy uses genetically engineered viruses to target and destroy cancer cells through stimulation of endogenous or viral based genetic programs. Gene-based immunotherapy includes (1) alteration of cancer cells to produce pro-inflammatory immune stimulating molecules, or highly antigenic protein genes to stimulate immune recognition; (2) in vivo delivery of immunomodulatory genes, mainly cytokines, to the tumor sites; and (3) alteration of immune cells from patients to target cancer cells.6 Unfortunately, systemic administration of viral vectors is currently not an effective method for targeting metastatic disease due to low initial viral titers, immune inactivation, nonspecific adhesion and loss of particles. The efficiency of gene transfer through nonviral techniques is also very low. The current challenge for cancer gene therapy is to achieve efficient and safe delivery of therapeutic genes to the malignant cells. Given the limitations of current technologies this is a particularly daunting task for metastatic disease.
Gene-modified cell therapy uses gene transfer and cell-based technologies in a complementary fashion to insulate appropriate gene expression cassettes with cell carriers that chaperone them to sites of active tumor growth. Specific targeting vectors can incorporate molecular features that optimize expression and secretion of the transported genes within the environment of a functional cell vehicle. Gene-modified cell therapy has the potential to both complement the positive aspects and mitigate the negative features of each therapy used as a single agent approach.
Cell vehicles for prostate cancer
Currently, gene-modified cell therapy utilizes two general cell types as vehicles: terminally differentiated, postmitotic, long-lived cells and stem/progenitor cells. There are several types of cells within these two general groups that can home to sites of tumor growth. Possibilities among differentiated cell carriers include specific immune cells, for example, macrophages, T cells, natural killer (NK) cells and eosinophils.7, 8 The use of immune cells in gene-modified cell-based vaccine strategies can be considered as gene-modified cell-based therapy, but this area of research is not the focus of this review. Adult stem cells are also candidate cell vehicles in regenerative medicine and potentially for cancer therapy.9 Notable examples of gene-modified cell therapy include the use of ex vivo expanded and gene-modified tumor-specific T cells to treat cancer patients,10 and infusion of bone marrow cells (BMCs) transduced with a normal adenosine deaminase gene to treat patients with severe combined immunodeficiency.11 The application of gene-modified cell therapies may also provide opportunities for the development of effective systemic therapy for patients with advanced prostate cancer.
Differentiated immune cell vehicles
Immunotherapy has been tested extensively in preclinical models and to some extent in clinical trials for prostate cancer.12 Tumor-specific cytotoxic T lymphocytes (CTLs) have been shown to migrate into both animal and human tumors.13, 14, 15 CTLs can discriminate tumor cells based on subtle alterations in peptides displayed in association with MHC (major histocompatability complex) molecules at the cell surface.16 Early trials sought to exploit intrinsic T-cell-mediated target cell killing and demonstrated localization of adoptively transferred T cells to sites of tumor growth.14, 17, 18 Unfortunately, there was also extensive localization to other organs such as the liver and spleen, with potential for toxicity. More recent advances have augmented the intrinsic cytotoxicity of T cells through gene transfer of cytokines such as interleukin-2 or granulocyte-macrophage colony-stimulating factor.19 In addition, the ability to identify different subsets of T cells that infiltrate into tumors has become more sophisticated.20 As a result, clinical trials have been carried out using both MHC-restricted T cells (presumably tumor antigen specific) and NK cell subsets with additional activation by cytokines such as interleukin-2.21, 22
Most malignant tumors contain large numbers of macrophages as a major component of their leukocytic infiltrate.23, 24, 25 These tumor-associated macrophages arise from monocyte precursors that migrate from the blood stream into both primary and secondary tumors at an early stage in their development. Tumor-associated macrophages have the potential to mediate tumor cytotoxicity directly through the release of pro-apoptotic cytokines and nitric oxide and phagocytosis, and indirectly through cytokine-mediated stimulation of lymphocytes. Tumor-associated macrophages transduced with murine IL-12 recombinant adenoviral vector (AdIL-12) not only provide a stable cellular vehicle for transfer of this highly active immuno-modulatory gene, but also promote direct and indirect macrophage-specific antitumor effects.26 Human prostate cancer tissues have hypoxic regions that contain large numbers of macrophages.27, 28 To exploit this biological milieu, macrophages can be modified ex vivo with hypoxia response elements to regulate therapeutic genes specifically hypoxic for regions of tumors.28, 29 The limitation of using macrophages as a cellular vector to deliver therapeutic genes is that over time they can promote a mitogenic and/or pro-angiogenic phenotype in tumors.30
Dendritic cells (DCs) are potent antigen-presenting cells that have the capacity to prime antigen-specific immune responses mediated by CD4+ and CD8+ lymphocytes. Autologous DC can be isolated, pulsed ex vivo with specific tumor antigen or peptide and re-administered to the host to prime specific antitumor responses. However, the major disadvantages of this approach include the requirement for matching defined peptides with MHCs and the short-time duration of antigen presentation.31 Although DCs are primarily considered for cancer vaccine applications, their capacity for homing to sites of tumor accumulation and transducibility make them candidates for various gene-modified cell therapy approaches.31, 32, 33
Stem/progenitor cell vehicles
The identification of reservoirs of multipotential stem cells within adult tissue provides exciting prospects for novel therapeutic approaches, such as cell-based tissue engineering and stem cell-mediated gene therapy. Stem cells have the remarkable potential of self-renewal and differentiation into many different cell types. Transduction of stem cells can introduce genes into multiple cell lineages and lead to stable expression of the transgene for long periods of time. The discovery of stem cell plasticity revealed significant opportunities for all types of cell-based therapy34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 and provided insight into the molecular and functional heterogeneity of stem cell populations and understanding of their transdifferentiation potential.47, 48
Hematopoietic stem cell vehicles
Bone marrow is a unique and accessible source of multiple lineages of cells with potential therapeutic value, especially hematopoietic progenitor and stem cells. BMCs are an optimal cell vehicle, because these cells can be easily isolated, expanded and genetically modified ex vivo and reinjected into the patient. Importantly, hematopoietic stem cells (HSCs) have the capacity to home to BM.49, 50 Since adult stem cells can be isolated from the patient's own tissue, they are genetically matched and are not be rejected by the patient's immune system. Over the past two decades, the ability to transfer genes into HSC has provided new insights into the behavior of individual stem cells and offered a novel approach for the treatment of various inherited or acquired disorders. At present, gene transfer into HSC has been achieved mainly using modified retroviruses. However, as long-lived, continuously replicating cells, HSCs accumulate mutations throughout their lifespan. In the context of their proliferation and differentiation capacities, HSCs are susceptible to the consequences of genetic alterations including retroviral vector insertion.
Cancer treatment through autologous BM transplantation, was one of the first clinical applications for HSC gene transfer technology. Following initial gene marking studies,51 the use of gene therapy for cancer expanded to become a dominant clinical application for gene therapy. Transfer of drug-resistance genes into HSC, combined with dose intensification of chemotherapeutic agents, has been applied to autologous BM transplantation to treat various tumors.52, 53 Recent reports of combination therapy with immune cytokines and BM transplantation appear to provide specific advantages and a new direction for cancer therapy.54, 55
Mesenchymal stem cell vehicles
The adherent fraction of BMCs contains differentiated mesenchymal BM stromal cells and pluripotent mesenchymal stem cells (MSCs) that give rise to differentiated cells that belong to the osteogenic, chondrogenic, adipogenic, myogenic and fibroblastic lineages.38 Solid tumors are composed of both tumor cells and supportive tumor stroma. Tumor stroma consists of four main elements: (a) tumor vasculature, (b) immune cells, (c) extracellular matrix and (d) fibroblastic stromal cells—also known as tumor-associated fibroblasts.56, 57 During tumor formation in particular, tissue remodeling occurs, with mesenchymal cells contributing to the stromal support element of the tumor. Recent evidence suggests that MSCs are ideal candidates for cellular delivery vehicles, which can home into the tumor stroma and deliver therapeutic agents.58 There have been many attempts to use MSCs as cellular delivery vehicles for therapeutic gene products (such as interleukin-3, growth hormone and factor IX) via the systemic circulation. When MSCs were systemically injected into mice with subcutaneously established tumors, MSC-derived fibroblasts were consistently identified in the tumors but not in healthy organs.59 Exogenously administered MSCs migrate to and preferentially survive and proliferate within the tumors. Once in the tumor microenvironment, MSCs are incorporated into the tumor architecture, where they serve as precursors for stromal elements, predominantly fibroblasts.58, 59, 60, 61
Endothelial progenitor cell vehicles
Endothelial progenitor cells (EPCs) are a circulating, BM-derived cell population that are functionally and phenotypically distinct from mature endothelial cells. They can differentiate into endothelial cells in vitro and contribute to vasculogenesis and/or vascular homeostasis in vivo.62 To participate in postnatal vasculogenesis or endothelial repair, BM-derived EPC must respond to signals to mobilize from the BM, home to the site of ongoing vascular development, and differentiate into mature endothelial cells. Vascular trauma (for example, limb ischemia and myocardial infarct) releases signals into the circulation such as vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) that promote the mobilization of EPCs into the circulation.63 Moreover, local concentrations of VEGF and SDF-1 are elevated in ischemic foci and contribute to EPC recruitment from the circulation to the site of injury.64 The study that first identified a potential role of EPCs in tumor neovascularization used an adult immunodeficient mouse model engrafted with BM from mice carrying a transgene expressing β-galactosidase (lacZ) from endothelial-specific promoters.65 Moore et al.66 demonstrated that systemically transplanted EPCs home into brain tumors with a high specificity. The observation of BM-derived cells within the tumor vasculature and stroma led to the hypothesis that BM-derived cells contribute to tumor expansion in two distinct ways: by supplying EPCs that directly incorporate into the vascular endothelium of the tumor and by contributing cells that home to perivascular sites within the tumor and secrete pro-angiogenic growth factors.
Stem cell homing to bone marrow
An ideal choice among cell carriers would be stem cells that have the capacity to home to BM.49, 50 Over the past decade, remarkable advances have been made in characterizing the complex sequence of events involved in HSC homing to the BM. Homing is a coordinated multistep process that involves signaling by SDF-1 and stem cell factor; activation of lymphocyte function-associated antigen-1, very late antigen-4/5 and CD44; cytoskeleton rearrangement; membrane type 1 matrix metalloproteinase (MMP) activation; and secretion of MMP2/9.67 SDF-1 is a member of the chemokine family and is expressed by both BM stromal cells and endothelial cells.67 The SDF-1–CXCR4 axis is involved in directing normal HSC and metastatic cancer stem cell trafficking/metastasis to organs that highly express SDF-1 (for example, lymph nodes, lung, liver and bone).68, 69 The stem cell niche in adult somatic tissues plays an essential role in maintaining stem cells or preventing tumorigenesis by providing primarily inhibitory signals for both proliferation and differentiation.70 However, the niche also provides transient signals for stem cell division to support ongoing tissue regeneration. The balance between proliferation-inhibiting and proliferation-promoting signals is the key to homeostatic regulation of stem cell maintenance versus tissue regeneration. Along with advances in cell harvest and manipulation, stem cell differentiation and gene transduction technology, it is possible to generate stem cell carriers that home to the BM, the major site of prostate cancer metastasis.
Reprogrammed adult cells
Although cell differentiation involves complex genetic and epigenetic changes, it is now possible to generate cells with many properties of pluripotent embryonic stem cells by retroviral transduction of differentiated cells with only four transcription factors: Oct3/4, Sox2, Klf4 and c-Myc.71 The recent, stunning work of Yamanaka72 and Thomson73 demonstrated that normal human skin cells could be reprogrammed into induced pluripotent cells that had characteristics similar to human embryonic stem cells. Although this field of research is in its infancy, it is possible to speculate that future gene-modified cell therapy strategies will involve reprogramming the differentiation status of the cell vehicle and also supplying it with a payload therapeutic gene(s).
Gene therapy strategies for prostate cancer
In general, primary localized prostate cancer is slow growing and, therefore, allows significant time for testing, evaluation and adjustment of treatment strategies as compared with other malignancies. These clinical realities have led to a relatively high level of interest in various gene therapy approaches, in particular those that involve adenoviral vector-based delivery. Various gene therapy approaches including gene replacement, oncolytic virotherapy and gene-based immunotherapy have been developed specifically for prostate cancer applications and many have been tested in clinical trials. Below we discuss selected gene therapy strategies for prostate cancer.
Restitution of normal tumor suppressor gene function has been considered a legitimate agent for in vivo corrective gene therapy aimed at various molecular targets, including p53, retinoblastoma, cell-cycle control genes p16 and p21, and certain cell adhesion molecules. The tumor suppressor gene, p53, has an important role in sensing and repairing DNA damage, inhibiting the cell cycle to allow DNA repair and inducing apoptosis in severely damaged cells. Intra-prostatic injections of INGN 201, a replication defective adenoviral vector encoding a CMV-driven wild-type p53 gene, induced tumor cell apoptosis in both animal models of prostate cancer74 and in a Phase I clinical trial.75 Another pro-apoptotic gene, bax, has been studied with replication defective adenoviruses encoding bax to induce cancer cell apoptosis in animal models of prostate cancer, both with a constitutive promoter76 and with a prostate-specific promoter.77, 78 Ectopic re-expression of the cell surface receptor protein p75 neurotrophin receptor (p75NTR) in prostate cancer cell lines has also been shown to increase the frequency of tumor cell apoptosis and reduce the rate of cellular proliferation in vitro and in vivo.79 Another promising gene that exhibited antitumor activity in a preclinical model of prostate cancer is the mouse glioma pathogenesis-related protein 1 (Glipr1) gene, which is a direct target of p53. Administration of the AdGlipr1(AdRTVP-1) in an orthotopic metastatic murine prostate model resulted in extension of animal survival by diverse effects such as reduced metastasis to lung, suppression of tumor-associated angiogenesis, and increased infiltration of macrophages, DC and CD8+ T cells into the tumor.80
Cytotoxic/oncolytic gene therapy
Cytotoxic or cytolytic gene therapy is a strategy of transfer of drug-susceptible (suicide) genes or pro-apoptotic genes. The “suicide” gene strategy uses a gene encoding an enzyme that converts a nontoxic prodrug into a cytotoxic form when transfected into tumor cells. Herpes simplex virus thymidine kinase (HSV-tk) and the Escherichia coli cytosine deaminase (CD) genes are two common suicide gene therapy systems. HSV-tk converts nontoxic nucleoside analogs such as ganciclovir into phosphorylated compounds that act as chain terminators of DNA synthesis, while the prodrug 5-fluorocytosine is activated by CD. Tumor cell killing is achieved by necrosis and apoptosis. Both of these have been tested in animal models of prostate cancer.81 As a single agent82 or in combination with CD gene83 and/or radiotherapy,84, 85, 86 the HSV-tk system has shown minimal toxicity and led to reduced prostate-specific antigen (PSA) level in clinical trails.
Oncolytic vectors are designed to infect cancer cells and induce cell death through the propagation of the virus, expression of cytotoxic proteins and cell lysis.87 With regards to viral replication pathways that could discriminate between cancer cells and normal ones, Ad 55kd E1b protein can inactivate tumor suppressor p53, and p53 is frequently inactivated in tumors. A 55kd E1b-deleted adenovirus, ‘dl1520’ or ‘ONYX-015’, was designed to replicate only in p53-defective tumor cells but not in normal cells.88 This adenovirus showed activity in multiple tumor models and was tested in various clinical trials.89 An alternative strategy involving the use of oncolytic virus that has been tested in prostate cancer is to employ a tissue-specific promoter to control the expression of adenovirus E1A and E1B proteins, which are key regulators of viral life cycle. As many prostate-specific gene regulatory systems have been developed, the promoters of PSA, PSMA and OC are excellent candidates to control prostate epithelial cell selective adenovirus replication.81 The first prostate-restricted replicative adenovirus was Calydon virus (CV706), which was engineered by placing the Ad E1A gene under the control of the minimal PSA promoter and enhancer sequences. The E1A expression of CV706 was limited to PSA-positive LNCaP human prostate cancer cells, and antitumor activity was demonstrated against LNCaP tumor xenografts.90
Immunomodulatory strategies in prostate cancer gene therapy
Activation of the immune system to recognize tumor cell antigens has been a target of many immunomodulatory approaches to cancer. An immune response toward tumor cells might be achieved by enhancing expression of a tumor cell antigen.91 Putative tumor-associated antigens including PSA,91, 92 PSMA,93 PAP,94 MUC-195 and NY-ESO96 have been tested or proposed for use as prostate cancer vaccines. However, the antigenic properties of these proteins are not optimal and multiple clinical trials that have tested these proteins as full-length proteins or peptide derivatives as primary vaccines have, in general, failed to show significant clinical responses.7, 97
Transfection/transduction of tumor or immune cells with cytokine genes that stimulate the antitumor function of immune cells is also an important therapeutic consideration. Specific cytokines that have been tested include interleukin-2, which stimulates T cells,98 and granulocyte-macrophage colony-stimulating factor, which stimulates macrophages99 and neutrophils.100 IL-12 is a heterodimeric pro-inflammatory cytokine that induces the production of IFN-γ, favors the differentiation of helper T cells (Th1) and forms a link between innate resistance and adoptive immunity.101, 102 In vitro studies have also shown that IL-12 can enhance survival and proliferation of early multipotent hematopoietic progenitor cells and linage-committed precursor cells.103 The immunomodulating functions of IL-12 have provided the rationale for exploiting this cytokine as an anticancer agent. In general, clinical trials with recombinant IL-12 protein, used as a single agent or as a vaccine adjuvant, have shown limited efficacy in most instances.104, 105, 106 However, significant antitumor and antimetastatic activity of IL-12 has been documented in several preclinical studies involving direct adenoviral vector-mediated IL-12 gene transfer into prostate cancer, gene-modified cell therapy, or in vaccine strategies.107, 108, 109 Adenoviral vector-mediated IL-12 gene therapy clinical trials for prostate cancer have been initiated or are in the planning stages at various institutions. Further reports regarding these trials will likely yield important information regarding the use of IL-12 gene therapy for prostate cancer.
We identified a novel mouse gene, Glipr1, as a p53 target gene and homolog to human GLIPR1.110 GLIPR1 (glioma pathogenesis-related protein)111 or RTVP-1 (related to testes-specific, vespid and pathogenesis protein)112 had also been identified in human glioblastoma cells and shown to be a marker of myelomonocytic differentiation in macrophages.113 The GLIPR1 protein has high amino-acid homology with human testis-specific protein, TPX1, contains a putative signal peptide sequence and transmembrane domain, and is structurally similar to group 1 of plant pathogenesis-related proteins that are implicated in plants defense response to viral, bacterial and fungal infection.111, 114 Since the mammalian testis proteins, plant proteins and the insect venom Ag-5 proteins are all secreted, it was speculated that GLIPR1 is a secretory protein and may play a role in human immune system.114
Following the identification of Glipr1/GLIPR1 and initial characterization of the genes, we documented that GLIPR1 expression in human prostate cancer, especially in metastatic tumors, is significantly reduced compared with that in normal prostate, owing, in part, to methylation in the regulatory region of this gene in prostate cancer cells.115 Functional analysis revealed that overexpression of either Glipr1 or GLIPR1 induces apoptosis and suppresses colony formation in vitro in various mouse and human cancer cell lines, independently of p53 status.110, 115 Adenoviral vector-mediated delivery of Glipr1 into orthotopic mouse prostate cancer significantly suppressed tumor growth and metastasis to lung,80 while administration of a Glipr1 gene-modified tumor cell vaccine to mice had significant antitumor activity in a preclinical model of recurrent prostate cancer.116 This work led to a Phase I/II neoadjuvant clinical trial in prostate cancer that involves adenoviral vector-mediated GLIPR1 therapy prior to radical prostatectomy (IND13033).
The results from these studies revealed interesting and unique functional properties of Glipr1/GLIPR1. In addition to direct and specific pro-apoptotic activities against cancer cells, Glipr1/GLIPR1 suppressed angiogenic activities in vitro and in vivo and strongly stimulated antitumor immune responses that resulted in specific CTL activities.80, 116 Interestingly, all of these cell-type-specific autocrine/paracrine activities were consistent with efficient secretion of the protein and also with unique, coordinated cell-specific systemic tumor suppressor functions. Recent mechanistic analysis indicated that GLIPR1 upregulation increases the production of reactive oxygen species leading to apoptosis through activation of the c-Jun NH2-terminal kinase (JNK) signaling cascade.117
Gene-modified cell vehicles for prostate cancer
Gene-modified cell therapy approaches that focus on the delivery of therapeutic genes to prostate cancer have only been tested in limited studies. The role of the cell carrier is to home to or to be physically placed into the tumor environment, and, through endogenously and/or exogenously added functional antitumor activities, to provide direct and/or indirect therapeutic responses. Gene-modified cell therapies that utilize immunomodulatory genes hold promise in eliciting a targeted response against primary prostate cancer and disseminated disease. Below, we summarize selected gene-modified therapies that have been tested in animal models of prostate cancer.
IL-12 gene-modified macrophages
We recently reported the results of preclinical studies that tested in situ IL-12-modified macrophage therapy using a mouse model of primary prostate cancer. AdIL-12-transduced macrophages produced significant local growth control, decreased metastases and improved survival compared with control Adβgal-transduced cells.26 Significantly increased CD4+ and CD8+ T cells were demonstrated in AdIL-12-transduced macrophages compared with controls. Systemic antitumor immunomodulatory effects including enhanced NK activities, and CTL activities were also documented. Optimal isolation and transduction methods will need to be further established. However, these studies demonstrated that cytokine-modified macrophages should be considered for further studies including clinical trials.
IL-12 gene-modified bone marrow cells for targeting to bone metastases
In contrast to strong toxicity of systemic administration of recombinant human IL-12, gene therapy with myeloid progenitor cells transduced with IL-12 did not induce hematologic or tissue toxicities.118 The retroviral vector, DFG-mIL-12, expresses both IL-12 subunits (p35 and p40) from a polycistronic message utilizing internal ribosome entry site sequences. DFG-mIL-12 has been used to modify the activities of DCs that were introduced into weakly immunogenic tumors using a mouse model system.119 In our study, we administered adult BMCs that were mixed leukocytes and genetically modified by retroviral vector (DFG-mIL-12)-mediated IL-12 gene transduction in an experimental mouse model of prostate cancer metastasis.107 IL-12 gene-modified BMC produced significant antimetastatic effects in bone and lung with less bone metastasis formation and fewer metastatic lung colonies. IL-12 induced immune responses and nonspecific tumor cell killing were indicated by significantly elevated CTL and NK activities in mice treated with DFG-mIL-12-transduced BMC. The significantly increased CD4+ and CD8+ T-cell infiltration in lung metastases suggests a direct antitumor response in the local area. This study demonstrated the capacity of this approach to deliver IL-12 to disseminated disease and to induce systemic and therapeutic immunity.
We transplanted gene-modified BMC in mice with intact hematopoietic systems. The concept that myeloablation to open space is a prerequisite for marrow stem cell engraftment has been challenged by studies showing high rates of engraftment in non-myeloablated mice.120 Vaccination after non-myeloablative syngeneic stem cell transplantation can achieve stable mixed BM chimerism and generate significantly enhanced tumor-specific immune responses without inducing graft-versus-host disease.121 Since most prostate cancer patients do not receive high-dose chemotherapy, and therefore have intact, although compromised, hematopoietic systems, our model is more realistic and directly translatable to a clinical setting.
Previous BM transplantation studies have shown that donor HSC can effectively home to bone and contribute to short- and long-term hematopoiesis after unconditioned BM transplant.122 In our study, we demonstrated that a subpopulation of retroviral vector-transduced LacZ+ BMC homed to host BM within 3 days after treatment and migrated to peripheral blood and lung 3 weeks later. Although specific homing activities were associated with both DFG-mIL-12- and DFG-eGFP-transduced BMC, only DFG-mIL-12-transduced BMC produced significant antimetastatic activities in lung and bone. These results indicate that IL-12 expression was associated with the antimetastatic effects, yet, do not specify whether local and/or systemic concentrations of IL-12 protein stimulated the response.
In addition to local and systemic antimetastasis immune responses, mice treated with DFG-mIL-12-transduced BMC demonstrated a significant survival advantage compared with all control groups within the first 40 days of the follow-up period.107 This effect may be due to increased immune cell capacity resulting from IL-12-mediated proliferation and colony formation of hematopoietic progenitor cells. However, we did not have direct evidence that DFG-mIL-12-transduced BM stem cells differentiated into T cells and NK cells. Alternatively, the extended survival in mice treated with DFG-mIL-12-transduced BMC may result from direct stimulatory effects of IL-12 on differentiated immune cells and/or anti-angiogenic activities of IL-12 on metastases.123, 124 IL-12 transduction into BMCs is probably acting at multiple levels, stimulating T cells, NK cells and DCs in an autocrine fashion.
Systemically delivered therapy that includes targeting of bone disease will be necessary to clinically impact metastatic prostate cancer. Small molecules that target specific molecular pathways, for example, tyrosine kinase inhibitors, will likely have a positive therapeutic impact in the future. Viral vector-mediated gene therapy has been pursued extensively for prostate cancer applications. Unfortunately, systemic administration of viral vectors, manufactured according to current technologies, is not an effective method for targeting metastatic disease because of low initial viral titers, immune inactivation, nonspecific adhesion and loss of particles. However, novel biological therapies including gene-modified cell therapy have specific advantages that warrant further concentrated study and development toward clinical applications. Gene-modified cellular vectors are unlikely to be neutralized by an immune response, particularly as the cells used are likely to be autologous. Cellular vectors are also likely to be more flexible with regards to the site of administration, since, with optimized organ site homing capacities, systemic administration is feasible.
The capacity to select cell populations with homing properties from immune cell populations or stem/progenitor cell populations and to transfer therapeutic gene or gene combination into these cells prior to systemic administration is an exciting conceptual advance in cancer therapy. Recent development in adult cell reprogramming toward pluripotent cells represents an exciting possibility that could dramatically expand the potential of cell carriers used in gene-modified cell therapy applications.72, 73 However, additional discovery/development of specific therapeutic genes and gene combinations needs further attention. GLIPR1 represents a gene with optimal therapeutic activities, owing to its endogenous functions as a secreted tumor suppressor protein that affects multiple cell types in a coordinated fashion.110, 115, 116, 117 Certainly, this area of research is at a very primitive level of application. Extensive basic and preclinical studies lie ahead. Beyond these studies, well designed and executed clinical trials will be necessary. In our view, for treatment of prostate cancer bone metastases, gene-modified cell therapies including cytokine gene-modified BMCs,107 deserve further consideration, study and potentially testing in clinical trials.
Gene therapy has moved beyond the preclinical stage to experimental treatment of a variety of inherited and acquired diseases. For such therapy to be successful, genes must be efficiently delivered to target cells and gene products must be expressed for prolonged periods of time, in an optimal location and without toxic effects to the host. Progress in this area may be achieved through gene-modified cell therapy in which carrier cells are isolated, cultured, transduced with therapeutic genes and grafted back to the host. BMCs and potentially BM-derived stem cells are ideal candidates for cell vehicles that target therapeutic genes to bone metastases, a significant clinical dilemma in prostate cancer therapy (Figure 1). Specific research needs to be focused on the selection and development of novel therapeutic genes for gene-modified cell therapy. In our opinion, GLIPR1 is an ideal candidate for these applications. Gene-modified cell therapy is a point of convergence for the application of many recent advances in genetics, molecular and cellular biology, and developmental biology. It offers hope for the development of effective systemic therapies for prostate cancer and other malignancies.
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Wang, H., Thompson, T. Gene-modified bone marrow cell therapy for prostate cancer. Gene Ther 15, 787–796 (2008). https://doi.org/10.1038/gt.2008.37
- prostate cancer metastasis
- gene-modified cell therapy