Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Lewy body disease as a potential negative outcome modifier of glioblastoma treatment: a case report.

BACKGROUND: Elderly patients with glioblastoma are particularly susceptible to the adverse effects of ionizing radiation to the brain. This population also has an increasing prevalence of dementia in the successive seventh, eighth and nineth decade of life, and dementia with Lewy bodies is characterized by pathologic α-synucleins, proteins that take part in neuronal DNA damage repair. CASE PRESENTATION: We report a 77-year-old man, with a history of coronary artery disease and mild cognitive impairment, who experienced subacute behavioral changes over 3 months with wording-finding difficulty, memory loss, confusion, perseveration, and irritable mood. Neuroimaging studies disclosed a 2.5 × 2.4 × 2.7 cm cystic enhancing mass with central necrosis in the left temporal lobe of the brain. Gross total resection of the tumor revealed IDH-1 wild-type glioblastoma. After treatment with radiation and temozolomide chemotherapy, his cognitive status deteriorated rapidly, and he died from unexpected sudden death 2 months after radiation. Autopsy of his brain revealed (i) tumor cells with atypical nuclei and small lymphocytes, (ii) neuronal cytoplasmic inclusions and Lewy bodies that were positive for α-synuclein in the midbrain, pons, amygdala, putamen and globus pallidus, and (iii) no amyloid plaques and only rare neurofibrillary tangles near the hippocampi. CONCLUSIONS: This patient most likely had pre-clinical limbic subtype of dementia with Lewy bodies prior to his diagnosis of glioblastoma. The radiation and temozolomide that was used to treat his tumor may have accelerated neuronal damage due to induction of DNA breakage when his brain was already compromised by pathologic α-synucleins. α-Synucleinopathy could be a negative outcome modifier in glioblastoma patients.

Finite element analysis of Tumor Treating Fields in a patient with posterior fossa glioblastoma.

INTRODUCTION: Tumor Treating Fields (TTFields) are alternating electric fields at 200 kHz that disrupt tumor cells as they undergo mitosis. Patient survival benefit has been demonstrated in randomized clinical trials but much of the data are available only for supratentorial glioblastomas. We investigated a series of alternative array configurations for the posterior fossa to determine the electric field coverage of a cerebellar glioblastoma. METHODS: Semi-automated segmentation of neuro-anatomical structures was performed while the gross tumor volume (GTV) was manually delineated. A three-dimensional finite-element mesh was generated and then solved for field distribution. RESULTS: Compared to the supratentorial array configuration, the alternative array configurations consist of posterior displacement the 2 lateral opposing arrays and inferior displacement of the posteroanterior array, resulting in an average increase of 46.6% electric field coverage of the GTV as measured by the area under the curve of the electric field-volume histogram (EAUC). Hotspots, or regions of interest with the highest 5% of TTFields intensity (E5%), had an average increase of 95.6%. Of the 6 posterior fossa configurations modeled, the PAHorizontal arrangement provided the greatest field coverage at the GTV when the posteroanterior array was placed centrally along the patient's posterior neck and horizontally parallel, along the longer axis, to the coronal plane of the patient's head. Varying the arrays also produced hotspots proportional to TTFields coverage. CONCLUSIONS: Our finite element modeling showed that the alternative array configurations offer an improved TTFields coverage to the cerebellar tumor compared to the conventional supratentorial configuration.

Nucleolin Is a Functional Binding Protein for Salinomycin in Neuroblastoma Stem Cells.

The aim of this study is to illuminate a novel therapeutic approach by identifying a functional binding target of salinomycin, an emerging anticancer stem cell (CSC) agent, and to help dissect the underlying action mechanisms. By utilizing integrated strategies, we identify that nucleolin (NCL) is likely a salinomycin-binding target and a critical regulator involved in human neuroblastoma (NB) CSC activity. Salinomycin markedly suppresses NB CD34 expression and reduces CD34+ cell population in an NCL-dependent manner via disruption of the interaction of NCL with CD34 promoter. The elevated levels of NCL expression in NB tumors are associated with poor patient survival. Altogether, these results indicate that NCL is likely a novel functional salinomycin-binding target that exhibits the potential to be a prognostic marker for NB therapy.

Clinical activity and safety of atezolizumab in patients with recurrent glioblastoma.

PURPOSE: Glioblastoma is the most common primary malignant brain tumor. No standard treatment exists for recurrent disease. Glioblastoma is associated with an immunosuppressive tumor microenvironment. Immune checkpoint inhibitors, including atezolizumab (anti-programmed death-ligand 1), have demonstrated clinical activity in various cancers. Here, we present the safety and efficacy of atezolizumab in patients with glioblastoma from the phase 1a PCD4989g clinical trial (NCT01375842). METHODS: Eligible patients had confirmed recurrent glioblastoma and measurable disease per RANO criteria. Atezolizumab (1200 mg) was administered intravenously every 3 weeks until progression or unacceptable toxicity. Patients were monitored for safety; response was evaluated at least every 6 weeks. Baseline biomarkers were evaluated. RESULTS: All 16 patients enrolled had received prior chemotherapy, and 50% prior bevacizumab. Ten patients (63%) experienced a treatment-related event. No treatment-related grade 4-5 events were reported. All deaths occurred due to progression or during follow-up. One patient experienced a partial response (5.3 months); 3 experienced disease stabilization. The median overall survival was 4.2 months (range 1.2 to 18.8+ months). Association between peripheral CD4+ T cells and efficacy was observed. Two patients with IDH1-mutant tumors and 1 with a POLE-mutant tumor experienced ≥ 16 months survival. CONCLUSIONS: Atezolizumab was safe and well tolerated in this group of patients with recurrent glioblastoma. Our preliminary findings suggest that biomarkers, including peripheral CD4+ T cells and hypermutated tumor status, may help guide selection of patients with recurrent glioblastoma who might receive most benefit from atezolizumab therapy, supporting further atezolizumab combination studies in glioblastoma.

Skin toxicities associated with tumor treating fields: case based review.

The novel anti-mitotic based tumor treating fields (TTFields) is FDA approved for recurrent glioblastoma. Recently the phase III upfront trial combining the Novo TTF-100A device, called Optune, with temozolomide following concurrent radiation therapy and chemotherapy, demonstrated improvement in survival. Wider use of this novel therapy is expected. The most common adverse event is dermatologic, which dominates compared to the next most frequently observed adverse event of headaches, the incidence of which was even in both arms in the phase III registration trial for recurrent glioblastoma. Our case review outlines the presentation, treatment, and outcome of representative patients using TTFields. In summary, preventative strategies to inform and educate patients and operators can prevent many of these dermatological events. Skin toxicity in the setting of concurrent use of TTFields with other therapies such as bevacizumab is an unknown and will need to be closely followed.

Phase I study of low-dose metronomic temozolomide for recurrent malignant gliomas.

BACKGROUND: The treatment goal for recurrent malignant gliomas centers on disease stabilization while minimizing therapy-related side effects. Metronomic dosing of cytotoxic chemotherapy has emerged as a promising option to achieve this objective. METHODS: This phase I study was performed using metronomic temozolomide (mTMZ) at 25 or 50 mg/m2/day continuously in 42-day cycles. Correlative studies were incorporated using arterial spin labeling MRI to assess tumor blood flow, analysis of matrix metalloproteinase-2 (MMP-2) and MMP-9 activities in the cerebrospinal fluid (CSF) as surrogates for tumor angiogenesis and invasion, as well as determination of CSF soluble interleukin-2 receptor alpha (sIL-2Rα) levels as a marker of immune modulation. RESULTS: Nine subjects were enrolled and toxicity consisted of primarily grade 1 or 2 hematological and gastrointestinal side effects; only one patient had a grade 3 elevated liver enzyme level that was reversible. Tumor blood flow was variable across subjects and time, with two experiencing a transient increase before a decrease to below baseline level while one exhibited a gradual drop in blood flow over time. MMP-2 activity correlated with overall survival but not with progression free survival, while MMP-9 activity did not correlate with either outcome parameters. Baseline CSF sIL-2Rα level was inversely correlated with time from initial diagnosis to first progression, suggesting that subjects with higher sIL-2Rα may have more aggressive disease. But they lived longer when treated with mTMZ, probably due to drug-related changes in T-cell constituency. CONCLUSIONS: mTMZ possesses efficacy against recurrent malignant gliomas by altering blood flow, slowing invasion and modulating antitumor immune function.

Neurological presentations of intravascular lymphoma (IVL): meta-analysis of 654 patients.

BACKGROUND: Patients with intravascular lymphoma (IVL) frequently have neurological signs and symptoms. Prompt diagnosis and treatment is therefore crucial for their survival. However, the spectrum of neurological presentations and their respective frequencies have not been adequately characterized. Our aim is to document the spectrum of clinical symptoms and their respective frequencies and to create a clinical framework for the prompt diagnosis of IVL. METHODS: A comprehensive meta-analysis of 654 cases of IVL published between 1957 and 2012 was performed to provide better insight into the neurological presentations of this disease. Neurologic complications were mainly divided into central nervous system (CNS) and peripheral nervous system (PNS) presentations. RESULTS: There were no differences in occurrences of CNS IVL based on gender or geographic locations (Asian Vs non-Asian). However, most patients with CNS IVL were younger than 70 years of age (p < 0.05). Our limited data do not support the treatment efficacy of methotrexate. CNS symptoms were seen in 42% of all cases. The most common CNS complications identified were cognitive impairment/dementia (60.9%), paralysis (22.2%), and seizures (13.4%). PNS complications were seen in 9.5% of cases. Out of these, muscle weakness (59.7%), neurogenic bladder (37.1%), and paresthesia (16.1%) were the most common presentations. CONCLUSIONS: CNS complications are more common among IVL patients. Out of these, dementia and seizures outnumber stroke-like presentations.

An Overview of Alternating Electric Fields Therapy (NovoTTF Therapy) for the Treatment of Malignant Glioma.

As with many cancer treatments, tumor treating fields (TTFields) target rapidly dividing tumor cells. During mitosis, TTFields-exposed cells exhibit uncontrolled membrane blebbing at the onset of anaphase, resulting in aberrant mitotic exit. Based on these criteria, at least two protein complexes have been proposed as TTFields' molecular targets, including α/ß-tubulin and the septin 2, 6, 7 heterotrimer. After aberrant mitotic exit, cells exhibited abnormal nuclei and signs of cellular stress, including decreased cellular proliferation and p53 dependence, and exhibit the hallmarks of immunogenic cell death, suggesting that TTFields treatment may induce an antitumor immune response. Clinical trials lead to Food and Drug Administration approval for their treatment of recurrent glioblastoma. Detailed modeling of TTFields within the brain suggests that the location of the tumor may affect treatment efficacy. These observations have a profound impact on the use of TTFields in the clinic, including what co-therapies may be best applied to boost its efficacy.

An Evidence-Based Review of Alternating Electric Fields Therapy for Malignant Gliomas.

OPINION STATEMENT: Glioblastoma is a deadly disease and even aggressive neurosurgical resection followed by radiation and chemotherapy only extends patient survival to a median of 1.5 years. The challenge in treating this type of tumor stems from the rapid proliferation of the malignant glioma cells, the diffuse infiltrative nature of the disease, multiple activated signal transduction pathways within the tumor, development of resistant clones during treatment, the blood brain barrier that limits the delivery of drugs into the central nervous system, and the sensitivity of the brain to treatment effect. Therefore, new therapies that possess a unique mechanism of action are needed to treat this tumor. Recently, alternating electric fields, also known as tumor treating fields (TTFields), have been developed for the treatment of glioblastoma. TTFields use electromagnetic energy at an intermediate frequency of 200 kHz as a locoregional intervention and act to disrupt tumor cells as they undergo mitosis. In a phase III clinical trial for recurrent glioblastoma, TTFields were shown to have equivalent efficacy when compared to conventional chemotherapies, while lacking the typical side effects associated with chemotherapies. Furthermore, an interim analysis of a recent clinical trial in the upfront setting demonstrated superiority to standard of care cytotoxic chemotherapy, most likely because the subjects' tumors were at an earlier stage of clonal evolution, possessed less tumor-induced immunosuppression, or both. Therefore, it is likely that the efficacy of TTFields can be increased by combining it with other anti-cancer treatment modalities.

Technological Advances in the Treatment of Cancer: Combining Modalities to Optimize Outcomes.

The anticancer treatment modality tumor treating fields (TTFields; Optune, Novocure) use the lower frequency range of the electromagnetic spectrum to destroy tumor cells during mitosis. This treatment has been evaluated in several trials of patients with glioblastoma. In these patients, TTFields are delivered through 4 transducer arrays applied to the scalp. In a phase 3 clinical trial of patients with recurrent glioblastoma, TTFields were as effective as chemotherapy, and were associated with fewer and milder systemic toxicities. Data from a phase 3 trial in newly diagnosed glioblastoma suggested that the addition of TTFields to postoperative radiation therapy and chemotherapy represents an important advance in the management of newly diagnosed glioblastoma. Ongoing clinical trials are investigating the efficacy and safety of TTFields in other tumor types, including pancreatic cancer, mesothelioma, ovarian cancer, and non­small cell lung cancer. Other recent advances in the management of cancer have been seen with immunomodulatory therapy, including immune checkpoint inhibitors. Further study will be necessary to evaluate whether TTFields will enhance or impair other established and newly emerging therapies.

Contributors to contrast between glioma and brain tissue in chemical exchange saturation transfer sensitive imaging at 3 Tesla.

Off-resonance saturation transfer images have shown intriguing differences in intensity in glioma compared to normal brain tissues. Interpretation of these differences is complicated, however, by the presence of multiple sources of exchanging magnetization including amide, amine, and hydroxyl protons, asymmetric magnetization transfer contrast (MTC) from macromolecules, and various protons with resonances in the aliphatic spectral region. We report a study targeted at separating these components and identifying their relative contributions to contrast in glioma. Off-resonance z-spectra at several saturation powers and durations were obtained from 6 healthy controls and 8 patients with high grade glioma. Results indicate that broad macromolecular MTC in normal brain tissue is responsible for the majority of contrast with glioma. Amide exchange could be detected with lower saturation power than has previously been reported in glioma, but it was a weak signal source with no detectable contrast from normal brain tissue. At higher saturation powers, amine proton exchange was a major contributor to the observed signal but showed no significant difference from normal brain. Robust acquisition strategies that effectively isolate the contributions of broad macromolecular MTC asymmetry from amine exchange were demonstrated that may provide improved contrast between glioma and normal tissue.

On the importance of polar interactions for complexes containing intrinsically disordered proteins.

There is a growing recognition for the importance of proteins with large intrinsically disordered (ID) segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter-balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions.

Metabolomics of human cerebrospinal fluid identifies signatures of malignant glioma.

Cerebrospinal fluid is routinely collected for the diagnosis and monitoring of patients with neurological malignancies. However, little is known as to how its constituents may change in a patient when presented with a malignant glioma. Here, we used a targeted mass-spectrometry based metabolomics platform using selected reaction monitoring with positive/negative switching and profiled the relative levels of over 124 polar metabolites present in patient cerebrospinal fluid. We analyzed the metabolic profiles from 10 patients presenting malignant gliomas and seven control patients that did not present malignancy to test whether a small sample size could provide statistically significant signatures. We carried out multiple unbiased forms of classification using a series of unsupervised techniques and identified metabolic signatures that distinguish malignant glioma patients from the control patients. One subtype identified contained metabolites enriched in citric acid cycle components. Newly diagnosed patients segregated into a different subtype and exhibited low levels of metabolites involved in tryptophan metabolism, which may indicate the absence of an inflammatory signature. Together our results provide the first global assessment of the polar metabolic composition in cerebrospinal fluid that accompanies malignancy, and demonstrate that data obtained from high throughput mass spectrometry technology may have suitable predictive capabilities for the identification of biomarkers and classification of neurological diseases.

Body Fluids Modulate Propagation of Tumor Treating Fields.

Tumor treating fields (TTFields) are nonionizing alternating electric fields that have anticancer properties. After the initial approval for use in patients with recurrent glioblastoma in 2011 and newly diagnosed glioblastomas in 2015, they are now being tested in those with advanced lung cancer, ovarian carcinoma, and pancreatic cancer. Unlike ionizing radiation therapy, TTFields have nonlinear propagation characteristics; therefore, it is difficult for clinicians to recognize intuitively the location where these fields have the most impact. However, finite element analysis offers a means of delineating TTFields in the human body. Our analyses in the brain, pelvis, and thorax revealed that cerebrospinal fluid, edema, urine, ascites, pleural fluid, and necrotic core within a tumor greatly influence their distribution within these body cavities. Our observations thus provided a unified framework on the role of these compartmentalized fluids in influencing the propagation of TTFields.

Tumor-treating fields dosimetry in glioblastoma: Insights into treatment planning, optimization, and dose-response relationships.

Tumor-treating fields (TTFields) are currently a Category 1A treatment recommendation by the US National Comprehensive Cancer Center for patients with newly diagnosed glioblastoma. Although the mechanism of action of TTFields has been partly elucidated, tangible and standardized metrics are lacking to assess antitumor dose and effects of the treatment. This paper outlines and evaluates the current standards and methodologies in the estimation of the TTFields distribution and dose measurement in the brain and highlights the most important principles governing TTFields dosimetry. The focus is on clinical utility to facilitate a practical understanding of these principles and how they can be used to guide treatment. The current evidence for a correlation between TTFields dose, tumor growth, and clinical outcome will be presented and discussed. Furthermore, we will provide perspectives and updated insights into the planning and optimization of TTFields therapy for glioblastoma by reviewing how the dose and thermal effects of TTFields are affected by factors such as tumor location and morphology, peritumoral edema, electrode array position, treatment duration (compliance), array "edge effect," electrical duty cycle, and skull-remodeling surgery. Finally, perspectives are provided on how to optimize the efficacy of future TTFields therapy.

Neurocognitive assessment following whole brain radiation therapy and radiosurgery for patients with cerebral metastases.

The treatment of metastatic brain lesions remains a central challenge in oncology. Because most chemotherapeutic agents do not effectively cross the blood-brain barrier, it is widely accepted that radiation remains the primary modality of treatment. The mode by which radiation should be delivered has, however, become a source of intense controversy in recent years. The controversy involves whether patients with a limited number of brain metastases should undergo whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) delivered only to the radiographically visible tumours. Survival is comparable for patients treated with either modality. Instead, the controversy involves the neurocognitive function (NCF) of radiating cerebrum that appeared radiographically normal relative to effects of the growth from micro-metastatic foci. A fundamental question in this debate involves quantifying the effect of WBRT in patients with cerebral metastasis. To disentangle the effects of WBRT on neurocognition from the effects inherent to the underlying disease, we analysed the results from randomised controlled studies of prophylactic cranial irradiation in oncology patients as well as studies where patients with limited cerebral metastasis were randomised to SRS versus SRS+WBRT. In aggregate, these results suggest deleterious effects of WBRT in select neurocognitive domains. However, there are insufficient data to resolve the controversy of upfront WBRT versus SRS in the management of patients with limited cerebral metastases.

Methylphenidate Reversal of Executive Dysfunction in a Patient with Bi-Frontal Lobe Glioblastoma.

An elderly man with advanced glioblastoma developed neuro-cognitive deficits that were reversed by methylphenidate. After tumor resection from the right frontal lobe, he received cranial irradiation, temozolomide and Tumor Treating Fields (TTFields). MRI afterwards showed enhancements near the resection cavity and the contralateral frontal lobe. The patient experienced mild executive dysfunction that was not limiting his activities. Adjuvant temozolomide was started along with TTFields. After 2 cycles, his brain MRI showed stable disease, but he exhibited significant executive dysfunction. Methylphenidate improved his neuro-cognitive slowing in cycles 3 and 4. His disease eventually progressed during the 5th cycle, and he experienced a marked decline in activities. Repeat head MRI revealed tumor progression and cerebral edema. Treatments were discontinued while dexamethasone improved his neurological functions and bevacizumab biosimilar was later added. This case demonstrates the activity of methylphenidate for managing executive dysfunction in patients with glioblastoma while minimizing the use of dexamethasone.