Glioblastoma multiforme (GBM) remains one of the most lethal primary brain tumors despite surgical and therapeutic advancements. Targeted therapies of neoplastic diseases, including GBM, have received a great deal of interest in recent years. A highly studied target of GBM is interleukin-13 receptor α chain variant 2 (IL13Rα2). Targeted therapies against IL13Rα2 in GBM include fusion chimera proteins of IL-13 and bacterial toxins, nanoparticles, and oncolytic viruses. In addition, immunotherapies have been developed using monoclonal antibodies and cell-based strategies such as IL13Rα2-pulsed dendritic cells and IL13Rα2-targeted chimeric antigen receptor-modified T cells. Advanced therapeutic development has led to the completion of phase I clinical trials for chimeric antigen receptor-modified T cells and phase III clinical trials for IL-13-conjugated bacterial toxin, with promising outcomes. Selective expression of IL13Rα2 on tumor cells, while absent in the surrounding normal brain tissue, has motivated continued study of IL13Rα2 as an important candidate for targeted glioma therapy. Here, we review the preclinical and clinical studies targeting IL13Rα2 in GBM and discuss new advances and promising applications.

Summary The last decade has seen a dramatic increase in stem cell research that focuses on glioma stem cells and their mechanisms of action, revealing multiple potential targets for primary malignant brain tumors. We present a novel framework for considering glioma stem cell targets based on direct and indirect strategies. Direct strategies target glioma stem cells molecular pathways to overcome their resistance to radiation and chemotherapy, block their function or induce their differentiation. Indirect ones target the glioma stem cell microenvironment, namely the perivascular, hypoxic and immune niches. Progress made on glioma stem cell targets is reviewed in detail and specific pathways are identified in context of the proposed framework. The potential barriers for translation to the clinical setting are also discussed. Overall, targeting glioma stem cells provides an unprecedented opportunity for revolutionary approaches to treat high-grade gliomas that continue to have a poor patient prognosis.

Evidence has pointed to brain tumor stem cells (BTSC) as culprits behind human high-grade glioma (hHGG) resistance to standard therapy. Pre-clinical rodent models are the mainstay for testing of new therapeutic strategies. The typical model involves the intracranial injection of human glioma cells into immunocompromised hosts, hindering the evaluation of tumor-host responses and resulting in non-infiltrative tumors. The CT-2A model is an immunocompetent mouse model with potential to overcome these disadvantages. In this study, we confirmed the highly infiltrative nature of intracranial CT-2A tumors and optimized reproducible injection parameters. We then generated neurospheres and established, for the first time, the stemness of this model. CT-2A expression of the BTSC marker, CD133, increased from 2% in monolayer cells to 31% in fully-formed neurospheres. Investigation of three stem cell markers (Oct4, Nanog and Nestin) revealed a distinct stemness signature with monolayer cells expressing Oct4 and Nestin (no Nanog), and neurospheres expressing all three. Additionally, CT-2A cells were more proliferative and invasive than U87 cells, while CT-2A neurospheres were significantly more proliferative and invasive than either monolayer cells in vitro. Taken together, our results show that this model is a valuable tool for pre-clinical testing of novel therapeutics against hHGG and also affords the opportunity for investigation of BTSC in an immunocompetent setting.

Stem cells have generated great interest in the past decade as potential tools for cell-based treatment of human high-grade gliomas. Thus far, 3 types of stem cells have been tested as vehicles for various therapeutic agents: embryonic, neural, and mesenchymal. The types of therapeutic approaches and/or agents examined in the context of stem cell-based delivery include cytokines, enzyme/prodrug suicide combinations, viral particles, matrix metalloproteinases, and antibodies. Each strategy has specific advantages and disadvantages. Irrespective of the source and/or type of stem cell, there are several areas of concern for their translation to the clinical setting, such as migration in the adult human brain, potential teratogenesis, immune rejection, and regulatory and ethical issues. Nonetheless, a clinical trial is under way using neural stem cell-based delivery of an enzyme/prodrug suicide combination for recurrent high-grade glioma. A proposed future direction could encompass the use of stem cells as vehicles for delivery of agents targeting glioma stem cells, which have been implicated in the resistance of high-grade glioma to treatment. Overall, stem cells are providing an unprecedented opportunity for cell-based approaches in the treatment of high-grade gliomas, which have a persistently dismal prognosis and mandate a continued search for therapeutic options.

Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modality treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumor therapy is promising as it can be delivered in situ and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. In this article, we summarize the laboratory and clinical work using viral, cell-based, and synthetic vectors, as well as other strategies focused on potentiate gene delivery. Although tangible results on patients' survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. The enthusiasm of this progress needs to be tempered by the realistic assessment of the challenges needed to be overcome. Finally, as the field of gene delivery progresses, advances must be made in identifying genes and proteins key to the treatment of malignant gliomas. Due to the great heterogeneity of malignant glioma cells, only approaches combining different strategies may be ultimately successful in defeating this disease.

High-grade gliomas are among the most lethal of all cancers. Despite considerable advances in multi-modality treatment, including surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for malignant gliomas is promising as it allows in situ delivery and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. Viral vectors to deliver pro-apoptotic genes to malignant glioma cells have been investigated. Although tangible results on patients’ survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. Recently, cell-based gene delivery has been sought as an alternative method. In this paper, we report the pro-apoptotic effects of embryonic stem cell (ESC)-mediated mda-7/IL-24 delivery to malignant glioma cell lines. Our data show that these are similar to those observed using a viral vector. Additionally, acknowledging the heterogeneity of malignant glioma cells and their signaling pathways, we assessed the effects of conventional treatment for high grade gliomas, IR and TMZ, when combined with ESC-mediated transgene delivery. This combination resulted in synergistic effects on tumor cell death. The mechanisms involved in this beneficial effect included activation of both apoptosis and autophagy. Our in vitro data supports the concept that ESC-mediated gene delivery might offer therapeutic advantages over standard approaches to malignant gliomas. Our results corroborate the theory that combined treatments exploiting different signaling pathways are needed to succeed in the treatment of malignant gliomas.

A novel application of the 10 B(n,␣) 7 Li nuclear reaction for the treatment of rheumatoid arthritis is under investigation. Rheumatoid arthritis is characterized by a painful inflammation of the membrane ͑synovium͒ lining articular joints. Since the tissue targeted for treatment is the diseased synovial membrane and the goal is synovial ablation ͑''synovectomy''͒, the proposed treatment is called Boron Neutron Capture Synovectomy. Development of this therapeutic modality has been carried out in a number of areas, including the ex vivo and in vivo evaluation of 10 B in arthritic synovium, and the design and construction of a dedicated neutron beam assembly for joint irradiation. Ex vivo evaluation of boron uptake in human arthritic synovium using K 2 B 12 H 12 has demonstrated that 10 B concentrations of 550-2400 ppm are repeatedly obtained. Preliminary in vivo experiments in an arthritic rabbit model have shown that synovial boron concentrations of approximately 265-950 ppm are obtained at 15 min post intra-articular injection. With these uptake levels experimental evaluation of the efficacy of BNCS in the treatment of rheumatoid arthritis in an animal model can be carried out. Optimal neutron beams suitable for joint irradiation are shown to be lower in energy than those used for BNCT. An assembly comprising a graphite reflector surrounding a D 2 O moderator has been designed, constructed, and installed on the 4.1 MeV tandem electrostatic accelerator at MIT's Laboratory for Accelerator Beam Applications. Monte Carlo calculations predict a total therapy time of between 8.4 and 31 min for the human knee, depending on the charged particle reaction used; a particle beam current of 1 mA is assumed. Therapy times to treat a human finger joint range from 4 to 14 min for a 1 mA accelerator current. These treatment times are based on average 10 B in vivo uptake levels ͑observed experimentally in the rabbit knee͒ of 950 ppm and a 10 000 RBE-cGy treatment dose. It is concluded that Boron Neutron Capture Synovectomy, consisting of intra-articular injection of a 10 B-labeled compound followed by neutron irradiation of the joint, has considerable potential as a means of treating rheumatoid arthritis.

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