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ImportanceGlioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.ObjectiveTo investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.Design, setting, and participantsThis phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.InterventionsThe active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.Main outcomes and measuresThe primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.ResultsA total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P

BackgroundRindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma.MethodsIn this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour

Background Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. Results A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy. [ABSTRACT FROM AUTHOR]

The multifunctional protein - tissue inhibitor of metalloproteinases-1 (TIMP-1) - has been associated with poor prognosis in several types of cancers including glioblastomas. Glioblastomas are the most common and malignant primary brain tumor known for being highly invasive and resistant to therapy. New treatment strategies are continuously being explored and currently vascular endothelial growth factor (VEGF) inhibitors administered in combination with Irinotecan is the most promising second line treatment. TIMP-1 has been associated with decreased response to chemotherapy in breast and colorectal cancer and especially the family of topoisomerase (TOP) inhibitors, such as Irinotecan, has been suggested to be affected by TIMP-1. In the present study, we investigated whether a high TIMP-1 expression in glioblastoma cells played a role in TOP inhibitor resistance. We established two TIMP-1 over-expressing cell lines and evaluated the sensitivity towards the TOP1 inhibitor SN-38 and the TOP2 inhibitor Epirubicin using a viability and a cytotoxicity assay. In addition, we investigated the invasive features of the cells in a brain slice culture model as well as in an orthotopic xenograft model. The results showed that TIMP-1 over-expressing U87MG cell line sub-clones were significantly more resistant than the controls when exposed to SN-38 and Epirubicin. The same tendency was seen for the TIMP-1 over-expressing A172 sub-clones. No significant differences in invasion patterns were observed for TIMP-1 over-expressing sub-clones when compared to controls. In conclusion, the present study suggests that TIMP-1 over-expression reduces the effect of TOP inhibitors in the glioblastoma cell line U87MG. There was no significant effect of TIMP-1 over-expression on tumor cell invasion. The association found between TIMP-1 cellular levels and the effect of TOP inhibitors needs to be validated in clinical patient material. Pediatric supratentorial high-grade astrocytomas (pHGAs) and diffuse intrinsic pontine gliomas (DIPG) are devastating pediatric malignancies for which no effective therapies exist. Poly-(ADP-Ribose)-Polymerase (PARP) protein expression is found in ∼60% of DIPGs suggesting PARP may be a potential therapeutic target. PARP1/2 were characterized by Western-blotting in normal human astrocytes (NHA), pHGA cell lines (SJG2, SF-188), DIPG cell lines (DIPG-M, DIPG58), and one murine brainstem glioma cell line (mBSG). Cell viability in response to different dosages of Olaparib, Veliparib, or Niraparib was determined using the MTT Assay. PARP activity, apoptosis, and DNA damage was determined by Western blotting against PAR, cleaved PARP, and phosphorylated yH2AX, respectively. Cell cycle phases were analyzed using FACS and western blot for p21. Western blotting demonstrated that, compared with NHAs, PARP1 were highly expressed in SJG2, DIPG-M, and DIPG-58 cells. PARP2 expression was only detected in SJG2 cells. All PARP inhibitors reduced PARP activity as indicated by reduced PAR levels. Olaparib reduced SJG2, mBSG, DIPG58 and DIPGM cell viability at concentrations of 5 or 10uM uM (P < 0.05), Whereas Niraparib induced cytotoxicity at concentrations of 2uM and above (P < 0.05). Olaparib and Niraparib induced DNA damage and apoptosis in SJG2 at doses of 5, 10uM and 2, 5, 10uM, respectively. Niraparib induced G2 arrest in mBSG demonstrated by FACS and increased levels of p21 (P < 0.05). Our data provides in vitro evidence that PARP inhibition may be an effective therapeutic avenue for treatment of pHGA and DIPG. Furthermore while all PARP inhibitors suppress PARP activity not all PARP inhibitors reduce cell viability. Thus not all PARP inhibitors can be expected to be equally efficacious in a clinical trial setting. Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized yeast cytosine deaminase (CD) gene to tumors in orthotopic glioma models. Within infected cells, CD converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-FU. The combination of Toca 511 with oral extended release 5-FC (Toca FC), is currently in clinical trials for recurrent High Grade Glioma (HGG, NCT01156584 and NCT01470794). Temozolomide (TMZ), in combination with radiation therapy, is the most commonly used first-line chemotherapy treatment for patients with glioblastoma, the most common and aggressive form of primary brain cancer. A separate study (Takahashi et al., this meeting) addresses the potential radiation synergy with Toca 511/5-FC treatment. A subset of patients with certain genetic alterations does not respond well to TMZ treatment and the overall median survival for patients who respond remains poor, suggesting combinatorial approaches may be necessary to significantly improve patient outcomes. To determine whether Toca 511 and 5-FC therapy is compatible with TMZ, we examined the effect of TMZ in combination with Toca 511 and 5-FC in TMZ-sensitive and resistant glioma lines both in vitro and in vivo. We show that in vitro TMZ delays but does not prevent RRV spread, nor interfere with Toca 511 and 5-FC mediated cell killing in glioma tumor cells, and in vivo there is no significant hematologic effect from the combination of 5-FC and the clinically relevant dose of TMZ. A synergistic long-term survival advantage is observed in mice bearing an orthotopic TMZ-sensitive glioma tumor after Toca 511 administration followed by co-administration of TMZ in combination with 5-FC. These results provide support for the investigation of this novel combination treatment strategy for patients with newly diagnosed glioblastoma. BACKGROUND: LAZ is a 21-aminosteroid that has radioprotective effects against radiation-induced lipid peroxidation. Also antiproliferative effects have been reported against glioblastoma cell lines. DESIGN/METHODS: LAZ PEGylated liposomes (Lipo G) were developed at the University of Houston.. Glioblastoma cell line U87-expressing firefly luciferase reporter gene (100,000 cells in 2 µL) was injected intracranially in each SCID mouse. There were 4 treatment groups (n = 8-9, each): brain model (M) without treatment (control), radiation 2Gy weekly (M + R), Lipo G at 5 mg/kg dose intraperitoneally twice per week (M + L) and radiation with Lipo G (M + R + L). Treatment lasted three weeks. Tumor size was monitored using bioluminescence imaging (BLI), in each mouse. Mice were sacrificed after 3 weeks. Brain was harvested. Lipid peroxidation of brain tissues was quantified by measuring malondialdehyde (MDA) as a surrogate biomarker. Survival was evaluated using Kaplan Meier analysis at P= 0.05. RESULTS: BLI intensity was 4002.03 ± 1737.67, 2034 ± 737.72, 1387.36 ± 684.53 and 2498.89 ± 2521.32 % for M, M + R, M + L and M + R + L, respectively. Tumor size of the M + L group was reduced by 65% compared to control. There was no significant difference in tumor size of radiated groups compared to control group. MDA brain concentration in M + L and M + R + L groups was significantly less than in M + R group (8.27 ± 0.78 and 10.37 ± 3.30 µM/gm vs. 23.09± 3.79 µM/gm). The survival mean was 22.67, 25.33, 25.22 and 27.13 days for M, M + R, M + R + L and M + L groups, respectively. Mean survival of LAZ treated groups (M + L and M + R + L) was significantly longer than that of the control group. CONCLUSIONS: LAZ liposomal formulations reduced tumor growth by 65%. LAZ also protected brain tissue from radiation-induced lipid peroxidation by reducing MDA concentration by 50%. These provocative data warrant further investigation of LAZ as a radiation protectant and chemotherapeutic agent. Patients with malignant brain tumors have a median survival of approximately one year following diagnosis, regardless of currently available treatments which include surgery followed by radiation and chemotherapy. Improvement in the survival of brain cancer patients requires the design of new therapeutic modalities that take advantage of common phenotypes. One such phenotype is the metabolic dysregulation that is a hallmark of cancer cells. It has therefore been postulated that one approach to treating brain tumors may be by metabolic alteration such as that which occurs through the use of the ketogenic diet (KD). The KD is high-fat, low-carbohydrate diet that induces ketosis and has been utilized for the non-pharmacologic treatment of refractory epilepsy. We and others have shown that this diet enhances survival and potentiates standard therapy in mouse models of malignant gliomas, yet the anti-tumor mechanisms are not fully understood. It has been previously shown that caloric restriction, which induces ketosis, reduces microvessel density in mouse and human brain tumor models, suggesting an anti-angiogenic effect. We now report that in animals fed KetoCal® (KC)(4:1 fat:protein/carbohydrates) ad libitum, peritumoral edema is significantly reduced early in tumor progression when compared to those fed a standard rodent diet. Gene expression profiling demonstrated that KC decreases the expression of the gene encoding vascular endothelial growth factor B (VEGFB) and angiopoetin 1 receptor (TEK). Furthermore, protein analysis showed a reduction of platelet endothelial cell adhesion molecule 1 (PECAM1/CD31) in tumors from animals maintained on KC. Taken together our data suggests that KC alters the angiogenic processes involved in malignant progression of gliomas. A greater understanding of the effects of the ketogenic diet as an adjuvant therapy will allow for a more rational approach to its clinical use.