scholarly journals Causes of drug resistance and glioblastoma relapses

2021 ◽  
Vol 11 (1) ◽  
pp. 101-108
Author(s):  
A. A. Mitrofanov ◽  
D. R. Naskhletashvili ◽  
V. A. Aleshin ◽  
D. M. Belov ◽  
A. Kh. Bekyashev ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Progression ◽  
Blood Brain Barrier ◽  
Evolutionary Dynamics ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Response To Therapy ◽  
Brain Barrier ◽  
T Cell Therapy ◽  
Blood Brain

Glioblastoma multiform^ is one of the most aggressive malignancies, wich standard of treatment not changed over the past decade, and the average life expectancy from diagnosis to death does not exceed two years in the most optimistic trials. The review examines the features of the glioblastoma microenvironment, its genetic heterogeneity, the development of recurrent glioblastoma, the formation of drug resistance, the influence of the blood-brain barrier and the brain lymphatic system on the development of immunotherapy and targeted therapy. Molecular subgroups of glioblastomas with an assumed prognostic value were analyzed. It was determined that numerous relationships between glioblastoma cells and the microenvironment are aimed at ensuring tumor progression, and also cause a state of reduced effector function of T cells. Data on the development of future molecular-targeted therapies for four types of cancer cells based on their different properties and response to therapy are summarized: primary GSC, RISC cells, and proliferating and postmitotic non-GSC fractions. The penetration of blood-brain barrier with chemotherapeutic drugs and antibodies currently remains the main limitation in the treatment of glioblastoma. The resulting analysis of the causes is reduced to the following conclusions. A detailed understanding of the evolutionary dynamics of tumor progression can provide insight into the related molecular and genetic mechanisms underlying glioblastoma recurrence. The most promising methods of treatment for glioblastoma are combined therapy using immune checkpoint inhibitors in combination with new treatment methods -vaccine therapy, CAR-T-cell therapy and viral therapy. A deeper study of the mechanisms of drug resistance and acquisition resistance, biology and subcloning clonal populations of glioblastoma and its microenvironment, with active consideration of combined trips to the treatment will increase the survival rate of patients, and may lead to stable remission of the disease.

scholarly journals Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1294
Author(s):  
Yogesh R. Suryawanshi ◽  
Autumn J. Schulze
Keyword(s):  
Immune Responses ◽  
Malignant Glioma ◽  
Blood Brain Barrier ◽  
Tumor Heterogeneity ◽  
Checkpoint Inhibitors ◽  
Oncolytic Viruses ◽  
Brain Barrier ◽  
Current Status ◽  
Blood Brain ◽  
Federal Authority

Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood–brain barrier, the immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to (1) optimize delivery of oncolytic viruses beyond the blood–brain barrier; (2) trigger inflammatory immune responses in and around tumors; and (3) use multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

scholarly journals CLRM-10. THE INTER-RELATIONSHIP BETWEEN MULTI-MODAL LONGITUDINAL BIOMARKERS OF NEURAL DAMAGE, INFLAMMATION, AND COGNITION AFTER CAR T CELLULAR THERAPY: A SINGLE-CENTER PROSPECTIVE OBSERVATIONAL TRIAL (NCT04614987)

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv3-iv3
Author(s):  
Omar Butt ◽  
Alice Zhou ◽  
Ken Lee ◽  
Gregory Wu ◽  
Sheng-Kwei Song ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cellular Therapy ◽  
Performance Testing ◽  
Cognitive Testing ◽  
Brain Barrier ◽  
Blood Draw ◽  
T Cell Therapy ◽  
Observational Trial ◽  
Blood Brain ◽  
Car T

Abstract BACKGROUND Immune effector cell associated neurotoxicity syndrome (ICANS) remains a devastating, frequent complication of chimeric antigen receptor (CAR) T cell therapy for advanced-stage hematologic malignancies. Symptoms range from encephalopathy and headaches to aphasia, strokes, and diffuse cerebral edema. Persistent mild cognitive symptoms have also been reported. Unfortunately, the underlying pathophysiology driving ICANS is poorly understood. Current proposed models center on systemic inflammatory changes leading to endothelial dysfunction, blood-brain barrier (BBB) breakdown, and systemic cytokine and/or monocytes infiltration into the central nervous system (CNS). However, these models do not integrate predisposing risk factors for the development of ICANS. We previously demonstrated that pre-infusion plasma neurofilament light chain (NfL), a marker of neurodegeneration, may predict development of ICANS. Early elevations in NfL suggest development of ICANS is also related to pre-existing neuroaxonal injury. The longitudinal relationship between latent neuroaxonal injury, blood brain barrier (BBB) integrity, neuroinflammation, and cognition remains unknown. METHODS This prospective, observational trial examines the relationship between multi-modal (blood, cerebrospinal fluid (CSF), neuroimaging) biomarkers and cognition in a cohort of twenty patients undergoing standard-of-care CAR T cellular therapy. Biomarkers for neural injury include blood and CSF NfL and volumetric measures derived from structural magnetic resonance imaging (MRI). Biomarkers for neuroinflammation include blood and CSF glial fibrillary acidic protein (GFAP) and qualification of white matter hyper-intensity burden on MRI. BBB integrity will be quantified using the serum/CSF albumin ratio. Finally, neuropsychological performance testing will assay cognitive performance across multiple cortical domains including attention, memory, and executive function. Participants will undergo a baseline (pre-infusion) examination, followed by evaluation (blood draw, voluntary lumbar puncture, MRI scan, and cognitive testing) on post-infusion day 3 (D3), D30, D90, and D180. The primary outcome is percent change in a given biomarker level. RESULTS/CONCLUSIONS This ongoing trial has 2 of 20 planned participants enrolled.

scholarly journals Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1134
Author(s):  
Manuela Gernert ◽  
Malte Feja
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Adverse Effects ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Invasive Procedure ◽  
Resistance Mechanisms ◽  
Brain Barrier ◽  
Blood Brain ◽  
Drug Concentrations

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

scholarly journals Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna Galstyan ◽  
Janet L. Markman ◽  
Ekaterina S. Shatalova ◽  
Antonella Chiechi ◽  
Alan J. Korman ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Brain Tumor ◽  
Blood Brain Barrier ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Brain Barrier ◽  
Systemic Delivery ◽  
Blood Brain

AbstractBrain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood–brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.

scholarly journals Blood–Brain Barrier in Brain Tumors: Biology and Clinical Relevance

2021 ◽  
Vol 22 (23) ◽  
pp. 12654
Author(s):  
Francesca Mo ◽  
Alessia Pellerino ◽  
Riccardo Soffietti ◽  
Roberta Rudà
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Phase 1 ◽  
Brain Barrier ◽  
Convection Enhanced Delivery ◽  
Cell Lung Carcinoma ◽  
Blood Brain

The presence of barriers, such as the blood–brain barrier (BBB) and brain–tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1–2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing.

scholarly journals Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment

2018 ◽  
Author(s):  
Anna Galstyan ◽  
Antonella Chiechi ◽  
Alan J. Korman ◽  
Tao Sun ◽  
Liron L. Israel ◽  
...  
Keyword(s):  
Immune Response ◽  
Brain Tumor ◽  
Blood Brain Barrier ◽  
T Regulatory Cells ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Brain Barrier ◽  
Blood Brain ◽  
Local Brain

AbstractTreatment of brain gliomas with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross the blood-brain barrier (BBB). We describe a new generation of nano immunoconjugates (NICs) developed on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 and/or a-PD-1 for delivery across the BBB and activation of local brain anti-tumor immune response in glioma-bearing mice. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) resulted in an increase of CD8+ T-cells with a decrease of T regulatory cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with combination of NICs was significantly longer compared to animals treated by single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of nanopolymer-conjugated checkpoint inhibitors as an effective treatment of GBM via activation of both systemic and local brain tumor immune response.

Liposomal Cytarabine (DepoCyte) for Treatment of Myeloid CNS Relapse in CML Occurring during Therapy with Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4556-4556
Author(s):  
Karl J. Aichberger ◽  
Susanne Herndlhofer ◽  
Hermine Agis ◽  
Wolfgang R. Sperr ◽  
Werner Rabitsch ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Clinical Symptoms ◽  
Local Therapy ◽  
Response To Therapy ◽  
Brain Barrier ◽  
Leukemic Cells ◽  
Molecular Response ◽  
Liposomal Cytarabine ◽  
Cns Relapse ◽  
Blood Brain

Abstract Central nervous system (CNS) relapse in chronic myeloid leukemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation or in those with a generalized myeloid relapse. The BCR/ABL tyrosine kinase (TK) inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood-brain-barrier. We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations could be detected. Both patients received intrathecal liposomal cytarabine (DepoCyte®) (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other patient, consecutive treatment with dasatinib (70 mg per os twice daily) was started. In response to therapy, the clinical symptoms resolved and the leukemic cells in the CSF disappeared in both patients. After four months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse. In conclusion, ‘anatomic’ resistance against imatinib in the CNS can lead to an (isolated) myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For treatment of patients with a systemic relapse involving the CNS and for prophylaxis, second-generation BCR/ABL TK inhibitors crossing the blood-brain-barrier such as dasatinib should be considered.

scholarly journals Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

2009 ◽  
Vol 12 (1) ◽  
pp. 46 ◽  
Author(s):  
Tripta Bansal ◽  
Manu Jaggi ◽  
Roop Khar ◽  
Sushama Talegaonkar
Keyword(s):  
Drug Resistance ◽  
Cancer Treatment ◽  
Blood Brain Barrier ◽  
Cancer Chemotherapy ◽  
Brain Barrier ◽  
Multi Drug Resistance ◽  
Cancer Drugs ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Anti Cancer

Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.

scholarly journals CYT387, a potent IKBKE inhibitor, suppresses human glioblastoma progression by activating the Hippo pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xin Wang ◽  
Jie Lu ◽  
Jing Li ◽  
Yang Liu ◽  
Gaochao Guo ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Blood Brain Barrier ◽  
Hippo Pathway ◽  
Brain Barrier ◽  
Migration And Invasion ◽  
Mouse Tumor ◽  
Glioblastoma Cell ◽  
Blood Brain ◽  
The Hippo Pathway

AbstractRecent studies have showed that IKBKE is overexpressed in several kinds of cancers and that IKBKE-knockdown inhibits tumor progression. In this article, we first verified that two glioblastoma cell lines, U87-MG and LN-229, were sensitive to CYT387 by measuring the half maximal inhibitory concentration (IC50) with a CCK-8 assay and then demonstrated that CYT387, as a potent IKBKE inhibitor, suppressed glioblastoma cell proliferation, migration and invasion. Additionally, CYT387 induced cell apoptosis and arrested the cell cycle at the G2/M checkpoint in vitro. Furthermore, we showed that CYT387 did not simply inhibit IKBKE activity but also decreased IKBKE expression at the protein level rather than at the mRNA level. We discovered that CYT387 restrained malignant tumor progression by activating the Hippo pathway in vitro. By coimmunoprecipitation (co-IP), we showed that IKBKE interacted with TEAD2 and YAP1, thus accelerating TEAD2 and YAP1 transport into the nucleus. In subsequent in vivo experiments, we found that CYT387 inhibited subcutaneous nude mouse tumor growth but had little impact on intracranial orthotopic xenografts, probably due to a limited ability to penetrate the blood–brain barrier (BBB). These results suggest that CYT387 has potential as a new antiglioblastoma drug, but an approach to allow passage through the blood–brain barrier (BBB) is needed.

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