Practical and translational therapeutic elements for GBM therapy.

Gene therapy offers a multidimensional set of approaches intended to treat and cure glioblastoma (GBM), in combination with the existing standard-of-care treatment (surgery and chemoradiotherapy), by capitalizing on the ability to deliver genes directly to the site of neoplasia to yield antitumoral effects. Four types of gene therapy are currently being investigated for their potential use in treating GBM: (i) suicide gene therapy, which induces the localized generation of cytotoxic compounds; (ii) immunomodulatory gene therapy, which induces or augments an enhanced antitumoral immune response; (iii) tumor-suppressor gene therapy, which induces apoptosis in cancer cells; and (iv) oncolytic virotherapy, which causes the lysis of tumor cells. The delivery of genes to the tumor site is made possible by means of viral and nonviral vectors for direct delivery of therapeutic gene(s), tumor-tropic cell carriers expressing therapeutic gene(s), and "intelligent" carriers designed to increase delivery, specificity, and tumoral toxicity against GBM. These vehicles are used to carry genetic material to the site of pathology, with the expectation that they can provide specific tropism to the desired site while limiting interaction with noncancerous tissue. Encouraging preclinical results using gene therapies for GBM have led to a series of human clinical trials. Although there is limited evidence of a therapeutic benefit to date, a number of clinical trials have convincingly established that different types of gene therapies delivered by various methods appear to be safe. Due to the flexibility of specialized carriers and genetic material, the technology for generating new and more effective therapies already exists.

Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors

Carrier Cell-based Delivery of an Oncolytic Virus Circumvents Antiviral Immunity

Fibrin microbeads (FMB) as a 3D platform for kidney gene and cell therapy

Advancing together and moving forward: Combination gene and cellular immunotherapies

MicroRNA-sensitive Oncolytic Measles Viruses for Cancer-specific Vector Tropism

Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.

VSV Oncolytic Virotherapy in the B16 Model Depends Upon Intact MyD88 Signaling

Recent studies indicate that cardiac transfer of adult stem cells can have a favorable impact on tissue perfusion and contractile performance of the infarcted heart. Several cell sources are being explored in an effort to regenerate infarcted myocardium, including hematopoietic stem cells, endothelial progenitor cells, cardiac resident stem cells, bone marrow–derived multipotent stem cells, and mesenchymal stem cells (MSCs). Each of these cell types may have its own profile of advantages, limitations, and practicability issues in specific settings. Studies comparing the regenerative capacity of distinct cell populations are scarce. Most clinical investigators have therefore chosen a pragmatic approach by using unselected bone marrow cells that contain different stem cell populations. Basic scientists, by contrast, are focusing more on specific cell populations in a quest to understand the biological foundations of cell therapy and to identify the most promising stem cells for cardiac regeneration.1 See p 214 MSCs are a rare population of self-renewing, multipotent cells present in adult bone marrow. Although MSCs represent <0.01% of all nucleated bone marrow cells, they can be readily expanded in vitro. In defined culture media, MSCs differentiate into several mesenchymal cell lineages, including cardiomyocytes.2,3 When injected into normal adult myocardium, MSCs differentiate into cardiomyocyte-like cells with sarcomeric organization.4 In an earlier study in pigs with myocardial infarction (MI), MSCs grafted into the infarcted area were shown to express muscle-specific markers and to improve regional wall motion.5 Ease of isolation, high expansion capability, and cardiomyogenic potential have led to the proposition that MSCs may be a good choice for cell-based therapies of MI.6 In a report published in this issue of Circulation , Dai et al7 have …

Glioblastoma multiforme (GBM) remains the most aggressive brain tumor, fatal within two years from diagnosis in most patients. Oncolytic viruses, such as oncolytic herpes simplex viruses (oHSVs), constitute a promising therapeutic approach in cancer (1). Yet, direct delivery of oHSV has shown clinical limitations in terms of efficacy. Duebgen et al. analyzed the role of oHSVs for the treatment of GBM by employing cell delivery systems based on the use of mesenchymal stem cells (MSCs) encapsulated in synthetic extracellular matrices (sECMs). Loading of MSCs with oHSVs demonstrated statistically significant advantages over direct delivery of oHSVs, in terms of efficacy, in clinical animal models of GBM (2). Engineering of oHSVs with tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) molecules further enhanced antitumoral responses and led to increased survival. While the study by Duebgen et al. represents a substantial advancement on the development of therapies against GBM, we also find issues that require further consideration. First, MSCs have demonstrated immunomodulatory roles affecting T-cells, B-cells, and dendritic cells (DCs) (3), as well as brain immunity through regulation of microglia (4). Immune cells synthesize cytokines mediating tissue inflammation, and inflammation has been linked to immune evasion, migration, and growth of several cancer types, including brain tumors (5). Therefore, the immunodeficient xenograft models used in this study might not fully recapitulate human physiology and, accordingly, the responses that MSCs might elicit in human patients. Indeed, it is widely accepted that inflammation should be considered when aiming at developing novel anticancer therapies. As MSCs can be readily isolated from rodents, autologous immunocompetent models might provide important information parallel to the use of xenograft heterologous transplantation experiments. Therefore, evaluating the role of inflammation remains critical for the future development of autologous therapies in humans, as suggested by the authors. Second, we also wondered whether the use of oHSVs-MSCs might provide additional beneficial effects in combination with standard strategies. MSCs are sensitive to various types of anticancer drugs (6) that could provoke changes in their behavior (eg, differentiation), or even induce apoptosis. An alternative possibility is that radio and chemotherapy effectively target the differentiated tumoral mass, whereas oHSVs-MSCs might provide a beneficial effect against glioma stem cells, populations presumably resistant to conventional therapies and responsible for tumor relapse, as well as patient death upon migration into the contralateral hemisphere. Last, TNF family members have demonstrated to drive basal glioma migration in syngeneic animal models (7). However, the study by Duebgen et al. (2) relies on the use of human cancer lines that hardly recapitulate the infiltrative properties of GBM. Therefore, it would be of interest to evaluate the antitumoral responses elicited upon TRAIL-loaded oHSVs in models more faithfully recapitulating human GBM infiltrative behavior.

What's in a Name?

Phase I Trial of Replication-competent Adenovirus-mediated Suicide Gene Therapy Combined with IMRT for Prostate Cancer

Chapter 15 - Gene/Viral Treatment Approaches for Malignant Brain Cancer

Glioblastoma multiforme (GBM) is a highly invasive brain tumour that is unvaryingly fatal in humans despite even aggressive therapeutic approaches such as surgical resection followed by chemotherapy and radiotherapy. Unconventional...

Targeting the Untargetable: Oncolytic Virotherapy for the Cancer Stem Cell