Mechanical Thrombectomy for Basilar Artery Occlusion with a Type 1 Persistent Proatlantal Artery: A Case Report and Literature Review.

Objective: Persistent proatlantal artery (PPA) is a primitive carotid-vertebrobasilar anastomosis (CVA); acute ischemic stroke due to basilar artery (BA) occlusion via a PPA is extremely rare. Case Presentation: An 84-year-old female developed disturbance of consciousness (Glasgow Coma Scale E2V1M5) and quadriparesis with a National Institutes of Health Stroke Scale score of 35. Head CT revealed early ischemic changes in the right temporal lobe, and a hyperdense vessel sign in the BA. Cerebral angiography showed that the left vertebral artery (VA) did not originate from the left subclavian artery or aortic arch. A left common carotid artery angiogram showed the presence of the left PPA originating from the left external carotid artery. Mechanical thrombectomy (MT) with contact aspiration using a Penumbra 5MAX ACE 60 aspiration catheter was performed, and successful recanalization was achieved after clot retrieval in the first attempt (thrombolysis in cerebral infarction scale 2b). MRI performed the following day, however, revealed a newly developed large hemorrhagic infarction in the pons, with no improvement in her symptoms (modified Rankin Scale score of 5 at 90 days). Conclusion: Although MT achieved successful recanalization of the BA via the PPA, her clinical symptoms did not improve, probably because of poor collateral circulation or the long length of the occlusion. In patients with acute vertebro-BA occlusion, if the VA does not originate from the subclavian artery or aortic arch, the presence of a primitive CVA should be considered.

Brain metastasis and intracranial leptomeningeal metastasis from malignant peripheral nerve sheath tumors: illustrative cases.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue tumors. Intracranial metastasis from MPNSTs is quite rare. OBSERVATIONS: The authors report on a 73-year-old male whose MPNST metastasized to the brain and a 32-year-old male with leptomeningeal metastasis from MPNST and review 41 cases of MPNST that developed intracranial metastasis, as reported in the literature. LESSONS: Brain metastasis and leptomeningeal metastasis of MPNSTs show different clinical courses and require pathology-specific treatment.

CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in primary central nervous system lymphoma.

BACKGROUND: Rituximab, high-dose methotrexate (HD-MTX), procarbazine and vincristine (R-MPV), has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), but predictive factors for response to R-MPV have not yet been investigated. Herein, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R-MPV. METHODS: We investigated the long-term clinical course and status of MYD88 and CD79B genes in 85 patients with PCNSL treated with R-MPV or HD-MTX treatment, and the correlation of these genetic mutations with prognosis. RESULTS: R-MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5-year progression-free and overall survival rates, respectively). While MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (p < 0.05). However, the association of CD79B Y196 mutation with a better prognosis was not observed in the HD-MTX cohort, which indicated that CD79B Y196 mutation was a predictive marker for a favorable response to R-MPV. Furthermore, we established an all-in-one rapid genotyping system for these genetic mutations. CONCLUSIONS: In conclusion, CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in PCNSL. The rapid identification of MYD88 L265P and CD79B Y196 mutations can be helpful not only for the accurate molecular diagnosis of PCNSL but also for the prediction of response to R-MPV.

Surgical management of brain metastasis as a part of systematic metastases from adenoid cystic carcinoma of the external auditory canal: illustrative case.

BACKGROUND: Adenoid cystic carcinoma (ACC) of the external auditory canal (EAC) is a rare tumor that accounts for approximately 5% of all EAC tumors. ACC is generally known as a slow-growing tumor, but patients often experience recurrence or distant metastasis in the long clinical course. While the major pattern of recurrence is pulmonary metastasis, brain metastasis of ACC of the EAC is rare. OBSERVATIONS: The authors describe the case of a 72-year-old male who was diagnosed with ACC of the EAC. Approximately 7 years later, brain magnetic resonance imaging revealed an intra-axial homogenously enhancing mass lesion that had no direct connection with the skull base in the left frontal lobe. The patient underwent tumor resection and histopathological examination revealed a mixture of cribriform and tubular patterns. The image and pathological characteristics of the tumor were similar to those of primary ACC or ACC from other sites of origin. LESSONS: While patients with ACC of the EAC often experience recurrence or distant metastasis in the long clinical course, they survive for a relatively long period of time, even though an optimal treatment has not been established. The authors therefore recommend surgical resection for brain metastasis of ACC of the EAC to improve neurological symptoms.

Primary central nervous system malignant lymphoma in a patient with rheumatoid arthritis receiving tocilizumab: illustrative case.

BACKGROUND: Although the risk of developing malignant lymphoma is higher in patients with rheumatoid arthritis (RA) than in the general population, primary central nervous system lymphoma (PCNSL) in patients with RA is extremely rare. In recent years, there has been concern that biological disease-modifying antirheumatic drugs (bDMARDs), widely administered to patients with RA, might increase the risk of cancer development. The authors report the first case of PCNSL in a patient with RA receiving the bDMARD tocilizumab. OBSERVATIONS: A 70-year-old man who was diagnosed with RA in 2010 was treated with low-dose methotrexate (MTX) from 2010 to 2015. Tocilizumab was commenced in 2012. In 2018, he developed gait disturbances, and gadolinium-enhanced magnetic resonance imaging showed multiple contrast-enhanced lesions in the basal ganglia and brain stem. Stereotactic brain biopsy led to the diagnosis of diffuse large B-cell lymphoma, and finally PCNSL was diagnosed. He was treated with five courses of MTX 3.5 g/m2, and his disease has been in remission for 34 months. LESSONS: Low-dose MTX and bDMARDs are associated with the concern of increased cancer risk in patients with RA. Because tocilizumab has been in use for a relatively short time, further accumulation of cases and careful follow-up are necessary.

Efficacy of cancer-specific anti-podoplanin CAR-T cells and oncolytic herpes virus G47Δ combination therapy against glioblastoma.

Glioblastoma is a devastating malignant brain tumor with a poor prognosis despite standard therapy. Podoplanin (PDPN), a type I transmembrane mucin-like glycoprotein that is overexpressed in various cancers, is a potential therapeutic target for the treatment of glioblastoma. We previously reported the efficacy of chimeric antigen receptor (CAR)-T cells using an anti-pan-PDPN monoclonal antibody (mAb; NZ-1)-based third-generation CAR in a xenograft mouse model. However, NZ-1 also reacted with PDPN-expressing normal cells, such as lymphatic endothelial cells, pulmonary alveolar type I cells, and podocytes. To overcome possible on-target-off-tumor effects, we produced a cancer-specific mAb (CasMab, LpMab-2)-based CAR. LpMab-2 (Lp2) reacted with PDPN-expressing cancer cells but not with normal cells. In this study, Lp2-CAR-transduced T cells (Lp2-CAR-T) specifically targeted PDPN-expressing glioma cells while sparing the PDPN-expressing normal cells. Lp2-CAR-T also killed patient-derived glioma stem cells, demonstrating its clinical potential against glioblastoma. Systemic injection of Lp2-CAR-T cells inhibited the growth of a subcutaneous glioma xenograft model in immunodeficient mice. Combination therapy with Lp2-CAR-T and oncolytic virus G47Δ, a third-generation recombinant herpes simplex virus (HSV)-1, further inhibited the tumor growth and improved survival. These findings indicate that the combination therapy of Lp2-CAR-T cells and G47Δ may be a promising approach to treat glioblastoma.

Mechanical Thrombectomy for Azygos Anterior Cerebral Artery Occlusion: A Case Report and Literature Review.

Objective: Azygos anterior cerebral artery (ACA) is a well-known anomaly of the second segment of the ACA. Although cases of intracerebral aneurysms related to this anomaly have been reported, acute ischemic stroke (AIS) related to the azygos ACA is extremely rare. Case Presentation: An 84-year-old man developed disturbance of consciousness (Glasgow Coma Scale [GCS] E3V1M5), quadriparesis and aphasia, with a National Institutes of Health Stroke Scale (NIHSS) score of 32. Magnetic resonance imaging (MRI) showed no early ischemic changes, although a head magnetic resonance angiogram (MRA) demonstrated a single A2 trunk without any A3 branches that were suspected bilateral ACA occlusions. Mechanical thrombectomy for the occluded A2 trunk with contact aspiration using a Penumbra 4MAX aspiration catheter was performed, and the clot was retrieved and complete recanalization was achieved after two attempts (Thrombolysis in Cerebral Infarction scale 3) without any complications (onset to recanalization time: 187 min). The final angiogram demonstrated the recanalization of the single A2 and bilateral A3 branches, so we diagnosed as azygos ACA occlusion. MRI performed the next day revealed several small infarctions in bilateral frontal lobes, but ischemic symptoms gradually improved. NIHSS score decreased to two in 2 weeks and modified Rankin Scale (mRS) score at 90 days was one. Conclusion: In this case, occlusion of the azygos ACA led to a large ischemic penumbra that spread widely and bilaterally in the ACA area, resulting in sudden onset of severe ischemic symptoms, including quadriparesis and aphasia. However, due to complete and rapid recanalization with contract aspiration, a large part of the ACA territory bilaterally was salvaged and the patient recovered extremely well.

Results of Mechanical Thrombectomy in Patients Aged ≥80 Years.

Objective: The effectiveness of mechanical thrombectomy (MT) for anterior circulation large vessel occlusion (LVO) is controversial in elderly patients. The aim of this study was to evaluate the efficacy of MT in octogenarians. Methods: One hundred and sixty-five patients who underwent MT for anterior circulation LVO between May 2014 and August 2019 at our institution were evaluated. Patients were divided into two groups, the elderly group (≥80 years) and non-elderly group (<80 years), and we compared the effective recanalization rate (Thrombolysis in Cerebral Infarction 2b-3), good outcome rate (modified Rankin Scale 0-2 at 90 days), time from groin puncture to recanalization (P to R), symptomatic intracranial hemorrhage (sICH), and mortality rate between them retrospectively. Eligible patients for MT were judged using the Japanese stroke guidelines, and the selection criteria were more carefully applied to elderly patients. Results: MT was performed on 48 elderly patients (29.1%) and 117 non-elderly patients (70.9%). On the other hand, 10 elderly patients (19.6%) and 5 non-elderly patients (5.4%) did not undergo MT even though they met the inclusion criteria. There were significantly fewer male patients and smokers in the elderly group, but other baseline and clinical characteristics were not significantly different between the groups. Effective recanalization (elderly 93.8% vs non-elderly 91.5%), good outcome (45.8% vs 60.7%), P to R (33.5 minutes vs 33.5 minutes), sICH (2.1% vs 4.3%), and mortality (8.3% vs 2.6%) were not significantly different between the two groups. Conclusion: When recanalization was achieved by strict preoperative evaluation of clinical conditions and imaging, MT may be safe and effective even for octogenarians or older patients.

A Case of Cerebral Tumor Embolism from Extracardiac Lung Cancer Treated by Mechanical Thrombectomy.

Cerebral tumor embolism is a rare cause of acute ischemic stroke, and extracardiac carcinoma is an extremely rare cause. A 34-year-old man who had been diagnosed with lung cancer developed right hemiparesis and aphasia, with the National Institutes of Health Stroke Scale (NIHSS) score of 17. Magnetic resonance imaging (MRI) showed early ischemic change in the insular cortex and frontotemporal lobe and left internal carotid artery (ICA) terminal occlusion was confirmed by magnetic resonance angiogram (MRA). Mechanical thrombectomy (MT) with contact aspiration by a Penumbra ACE 68, followed by combined technique with a stent retriever was performed, and a soft, fragile embolus was retrieved. Finally, good recanalization was achieved (Thrombolysis in Cerebral Infarction [TICI] scale 2b), and on the next day, the right hemiparesis and aphasia were improved. However, the patient's general condition gradually worsened, and 43 days after thrombectomy, he died from respiratory failure. The retrieved embolus was examined pathologically and diagnosed as mucoepidermoid carcinoma of the same type as his lung cancer. Chest computed tomography (CT) showed that tumor invaded the right pulmonary vein and left atrium; these findings suggested that a piece of the tumor in the left atrium flowed into the left ICA and caused the acute ischemic stroke.

Establishment and Characterization of a Novel Primitive Yolk Sac Tumour Cell Line, TC587.

BACKGROUND/AIM: Yolk sac tumour (YST) is a rare malignant ovarian germ cell tumour that often occurs in young women or adolescents and exhibits an unfavourable outcome. To evaluate the biological behavior of carcinomas in vitro, permanent tumour cell lines are required. However, previously, only a few human YST cell lines have been established. Therefore, we aimed to establish a novel YST cell line. MATERIALS AND METHODS: We established a novel YST cell line, TC587, from an adolescent patient with ovarian YST. RESULTS: The cell line expressed AFP and SALL4, the characteristics of YST. In addition, we evaluated somatic mutations using next-generation sequencing and revealed some pathogenic variants, including mutations in the NRAS, KIT, KMT2C, RSF1, and TP53 genes. CONCLUSION: The newly established TC587 cell line may represent an effective tool for developing treatments and conducting molecular analyses for YST.

CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains.

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)-transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1-based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM.

Papillary glioneuronal tumor with a high proliferative component and minigemistocytes in a child.

Papillary glioneuronal tumor (PGNT) is a rare type of primary brain tumor. Although PGNT has traditionally been defined as a clinically indolent neoplasm, several cases with high proliferative activity and tumor recurrence have recently been reported. We report a case of PGNT in a 12-year-old boy who presented with epilepsy and harbored a 64 mm cystic tumor with a high proliferative component in the right temporal lobe. (11) C-methionine positron emission tomography (PET) showed high uptake in the solid mass. Gross total resection of the tumor mass was achieved and the patient became seizure-free without any neurological deficits. Histologically, the tumor contained two distinct areas of a vasocentric papilliform structure and a desmoplastic component. Minigemistocytic cells and small necrotic regions were observed adjacent to the pseudopapillae. Immunohistochemical analyses revealed both glial and neuronal differentiation. The Ki-67 proliferation index was high (14%) in the area corresponding to the high uptake region in the (11) C-methionine PET. No tumor recurrence was observed 20 months after surgery. High proliferative PGNTs are rare and to our knowledge this is only the third pediatric case of PGNT with atypical features reported in the literature. Hence, we here review the reported cases of PGNT and discuss the clinical, radiological and histological features of this malignancy.

Peptide-based inhibition of the HOXA9/PBX interaction retards the growth of human meningioma.

BACKGROUND: Meningiomas are the most common type of intracranial tumor, accounting for between 24 and 30 % of primary intracranial tumors. Thus far, no biomarkers exist to reliably predict the clinical outcome of meningiomas. A previous genome-wide methylation analysis revealed that HOXA9 is one of the most functionally relevant biomarkers. In this study, we have examined whether HOXA9 is a potential therapeutic target in meningiomas, using HXR9, a peptide inhibitor of the interaction between HOXA9 and its cofactor PBX. METHODS: We determined the expression level of HOXA9 in human meningiomas, meningioma cell lines, and normal brain tissue. Meningioma in culture and in subcutaneous tumors was treated with HXR9. We also examined the disruption of HOXA9/PBX dimers. RESULTS: We first confirmed that HOXA9 is highly expressed in meningiomas, but not in normal brain tissue. The HXR9 peptide blocks the binding of HOXA9 to PBX, leading to an alteration of DNA binding, and subsequent regulation of their target genes. HXR9 markedly inhibited the growth of meningioma cells and subcutaneous meningeal tumors. CONCLUSION: There is no effective chemotherapy for meningiomas at present, and targeting the HOXA9/PBX interaction may represent a novel treatment option for this disease.

Adoptive transfer of genetically modified Wilms' tumor 1-specific T cells in a novel malignant skull base meningioma model.

BACKGROUND: Meningiomas are the most commonly diagnosed primary intracranial neoplasms. Despite significant advances in modern therapies, the management of malignant meningioma and skull base meningioma remains a challenge. Thus, the development of new treatment modalities is urgently needed for these difficult-to-treat meningiomas. The goal of this study was to investigate the potential of build-in short interfering RNA-based Wilms' tumor protein (WT1)-targeted adoptive immunotherapy in a reproducible mouse model of malignant skull base meningioma that we recently established. METHODS: We compared WT1 mRNA expression in human meningioma tissues and gliomas by quantitative real-time reverse-transcription polymerase chain reaction. Human malignant meningioma cells (IOMM-Lee cells) were labeled with green fluorescent protein (GFP) and implanted at the skull base of immunodeficient mice by using the postglenoid foramen injection (PGFi) technique. The animals were sacrificed at specific time points for analysis of tumor formation. Two groups of animals received adoptive immunotherapy with control peripheral blood mononuclear cells (PBMCs) or WT1-targeted PBMCs. RESULTS: High levels of WT1 mRNA expression were observed in many meningioma tissues and all meningioma cell lines. IOMM-Lee-GFP cells were successfully implanted using the PGFi technique, and malignant skull base meningiomas were induced in all mice. The systemically delivered WT1-targeted PBMCs infiltrated skull base meningiomas and significantly delayed tumor growth and increased survival time. CONCLUSIONS: We have established a reproducible mouse model of malignant skull base meningioma. WT1-targeted adoptive immunotherapy appears to be a promising approach for the treatment of difficult-to-treat meningiomas.

Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts.

BACKGROUND: Expression of miR-17-92 enhances T-cell survival and interferon (IFN)-γ production. We previously reported that miR-17-92 is down-regulated in T-cells derived from glioblastoma (GBM) patients. We hypothesized that transgene-derived co-expression of miR17-92 and chimeric antigen receptor (CAR) in T-cells would improve the efficacy of adoptive transfer therapy against GBM. METHODS: We constructed novel lentiviral vectors for miR-17-92 (FG12-EF1a-miR-17/92) and a CAR consisting of an epidermal growth factor receptor variant III (EGFRvIII)-specific, single-chain variable fragment (scFv) coupled to the T-cell receptor CD3ζ chain signaling module and co-stimulatory motifs of CD137 (4-1BB) and CD28 in tandem (pELNS-3C10-CAR). Human T-cells were transduced with these lentiviral vectors, and their anti-tumor effects were evaluated both in vitro and in vivo. RESULTS: CAR-transduced T-cells (CAR-T-cells) exhibited potent, antigen-specific, cytotoxic activity against U87 GBM cells that stably express EGFRvIII (U87-EGFRvIII) and, when co-transduced with miR-17-92, exhibited improved survival in the presence of temozolomide (TMZ) compared with CAR-T-cells without miR-17-92 co-transduction. In mice bearing intracranial U87-EGFRvIII xenografts, CAR-T-cells with or without transgene-derived miR-17-92 expression demonstrated similar levels of therapeutic effect without demonstrating any uncontrolled growth of CAR-T-cells. However, when these mice were re-challenged with U87-EGFRvIII cells in their brains, mice receiving co-transduced CAR-T-cells exhibited improved protection compared with mice treated with CAR-T-cells without miR-17-92 co-transduction. CONCLUSION: These results warrant the development of novel CAR-T-cell strategies that incorporate miR-17-92 to improve therapeutic potency, especially in patients with GBM.

Cytokine therapy.

Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins, which exert pleiotropic and redundant effects that promote growth, differentiation and activation of normal cells. Cytokines can have either pro- or anti-inflammatory activity and immunosuppressive activity, depending on the microenvironments. The tumor microenvironment consists of a variable combination of tumor cells, endothelial cells and infiltrating leukocytes, such as macrophages, T-lymphocytes, natural killer (NK) cells, B cells and antigen-presenting cells (APCs). Cytokine production acts as a means of communication in the tumor microenvironment. In this article, we review the cross-talk between cytokines in the tumor environment and the cytokine therapies that have been used till date for glioma treatment.

Peptide-pulsed dendritic cell vaccination targeting interleukin-13 receptor α2 chain in recurrent malignant glioma patients with HLA-A*24/A*02 allele.

BACKGROUND AIMS: Dendritic cell (DC)-based vaccination targeting tumor-associated antigens is an attractive approach to overcoming the limitations of current treatments for malignant gliomas (MG). Interleukin-13 receptor α2 chain (IL-13Rα2) is a promising target because of its abundant and specific expression in MG. We conducted a phase I trial of DC vaccination in patients with recurrent MG using two IL-13Rα2-derived peptides restricted to HLA-A*0201 and -A*2402. The objective was to evaluate the safety and clinical and immunologic responses. METHODS: Eight recurrent MG patients were enrolled. DC were generated from peripheral blood and pulsed with HLA-matched peptide; 1 × 10(7) DC were administered every 2 weeks for a maximum of six immunizations. The T-cell response in peripheral blood was evaluated by tetramer and ELISPOT assays in HLA-A*2402 patients. RESULTS: All enrolled patients except one completed at least four DC vaccinations. No severe adverse events were observed. A positive T-cell response was detected in two out of three evaluable HLA-A*2402 patients. One patient achieved stable disease for 16 months and another patient showed a dramatic regression for one lesion for 4 months. CONCLUSIONS: The regimen was feasible and safe, and the HLA-A*24-restricted peptide exhibited a capacity to induce immune responses. These results warrant further studies to evaluate whether add-on regimens to post-operative chemoradiotherapy delays recurrence in newly diagnosed MG patients.

Expression of antigen processing and presenting molecules in brain metastasis of breast cancer.

Defects in human leukocyte antigen class I antigen processing machinery (APM) component expression can have a negative impact on the clinical course of tumors and the response to T cell-based immunotherapy. Since brain metastases of breast cancer are of increasing clinical significance, the APM component expression levels and CD8(+) T cell infiltration patterns were analyzed in primary breast and metastatic brain lesions of breast cancer by immunohistochemistry. Comparison of unpaired 50 primary and 33 brain metastases showed lower expression of ß2-microglobulin, transporter associated with antigen processing (TAP) 1, TAP2 and calnexin in the brain lesions. Although no significant differences were found in APM component scores between primary breast and brain lesions in 15 paired cases, primary breast lesions of which patients eventually developed brain metastases showed lower levels of ß2-microglobulin, TAP1 and calnexin compared with breast lesions without known brain metastases. The extent of CD8(+) T cell infiltration was significantly higher in the lesions without metastasis compared with the ones with brain metastases, and was positively associated with the expression of TAP1 and calnexin. Furthermore, mouse tumor cells stably transfected with silencing hairpin (sh)RNA for TAP1 demonstrated a decreased susceptibility to cytotoxic T lymphocytes in vitro and enhanced spontaneous brain metastasis in vivo. These data support the functional significance of TAP1 expression in tumor cells. Taken together, our data suggest that patients with low or defective TAP1 or calnexin in primary breast cancers may be at higher risks for developing brain metastasis due to the defects in T cell-based immunosurveillance.

Glioma-initiating cells and molecular pathology: implications for therapy.

There is now compelling evidence that gliomas harbor a small population of cells, termed glioma-initiating cells (GICs), characterized by their ability to undergo self-renewal and initiate tumorigenesis. The development of therapeutic strategies targeted toward GIC signaling may improve the treatment of malignant gliomas. The characterization of GICs provides a clue to elucidating histological heterogeneity and treatment failure. The role of the stem cell marker CD133 in the initiation and progression of brain tumors is still uncertain. Here, we review some of the signaling mechanisms involved in GIC biology, such as phosphatase and tensin homolog (PTEN), sonic hedgehog, Notch, and WNT signaling pathways, maternal embryonic leucine-zipper kinase (MELK), BMI1, and Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling. In addition, we discuss the role of microRNAs in GICs by focusing on microRNA-21 regulation by type I interferon.

Retrovirally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen.

The isotype of epidermal growth factor receptor variant III (EGFRvIII) is often identified in glioblastomas. Previously, we created a mouse monoclonal antibody, 3C10 (IgG2b), that specifically recognized EGFRvIII, and a recombinant single-chain variable fragment of 3C10. The aim of the current study was to develop genetically engineered T cells, termed T-bodies, that express a chimeric receptor consisting of the 3C10 single-chain variable fragment coupled to signaling modules such as the CD3zeta (ζ) chain, for the treatment of tumors expressing mutant EGFR. After successful construction of the chimeric 3C10/CD3ζ T-cell receptor, its expression on the T-body was observed using western blotting and flow cytometry. The specificity of the T-body for EGFRvIII was evaluated using an interferon-gamma Elispot assay and a standard (51) Cr-release cytotoxicity assay. Furthermore, we demonstrated that the systemically delivered T-body infiltrated the intrabrain tumor and significantly delayed tumor growth. These results indicate that the T-body expressing the chimeric 3C10/CD3ζ T-cell receptor specifically recognized glioma cells expressing EGFRvIII. In conclusion, T-body-based immunotherapy appears to be a promising approach for the treatment of glioma.