Advancements in chimeric antigen receptor-expressing T-cell therapy for glioblastoma multiforme: Literature review and future directions.

Glioblastoma multiforme (GBM) is an aggressive cancer that has been difficult to treat and often requires multimodal therapy consisting of surgery, radiotherapy, and chemotherapy. Chimeric antigen receptor-expressing (CAR-T) cells have been efficacious in treating hematological malignancies, resulting in several FDA-approved therapies. CAR-T cells have been more recently studied for the treatment of GBM, with some promising preclinical and clinical results. The purpose of this literature review is to highlight the commonly targeted antigens, results of clinical trials, novel modifications, and potential solutions for challenges that exist for CAR-T cells to become more widely implemented and effective in eradicating GBM.

Discontinuation of Antiseizure Medications in Patients With Brain Tumors.

Patients with brain tumors will experience seizures during their disease course. While providers can use antiseizure medications to control these events, patients with brain tumors can experience side effects, ranging from mild to severe, from these medications. Providers in subspecialties such as neurology, neuro-oncology, neurosurgery, radiation oncology, and medical oncology often work with patients with brain tumor to balance seizure control and the adverse toxicity of antiseizure medications. In this study, we sought to explore the problem of brain tumor-related seizures/epilepsy in the context of how and when to consider antiseizure medication discontinuation. Moreover, we thoroughly evaluate the literature on antiseizure medication discontinuation for adult and pediatric patients and highlight recommendations relevant to patients with both brain tumors and seizures.

Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients.

Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro-oncology experts convened to provide practical clinical guidance for the off-label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low-molecular-weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT.

The Safety and Efficacy of Concurrent Immune Checkpoint Blockade and Stereotactic Radiosurgery Therapy with Practitioner and Researcher Recommendations.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown growing promise in the treatment of brain metastases, especially combined with stereotactic radiosurgery (SRS). The combination of ICIs with SRS has been studied for efficacy as well as increasing radiation necrosis risks. In this review, we compare clinical outcomes of radiation necrosis, intracranial control, and overall survival between patients with brain metastases treated with either SRS alone or SRS-ICI combination therapy. METHODS: A literature search of PubMed, Scopus, Embase, Web of Science, and Cochrane was performed in May 2023 for articles comparing the safety and efficacy of SRS/ICI versus SRS-alone for treating brain metastases. RESULTS: The search criteria identified 1961 articles, of which 48 met inclusion criteria. Combination therapy with SRS and ICI does not lead to significant increases in incidence of radiation necrosis either radiographically or symptomatically. Overall, no difference was found in intracranial control between SRS-alone and SRS-ICI combination therapy. Combination therapy is associated with increased median overall survival. Notably, some comparative studies observed decreased neurologic deaths, challenging presumptions that improved survival is due to greater systemic control. The literature supports SRS-ICI administration within 4 weeks of another for survival but remains inconclusive, requiring further study for other outcome measures. CONCLUSIONS: Combination SRS-ICI therapy is associated with significant overall survival benefit for patients with brain metastases without significantly increasing radiation necrosis risks compared to SRS alone. Although intracranial control rates appear to be similar between the 2 groups, timing of treatment delivery may improve control rates and demands further study attention.

Developing a computable phenotype for glioblastoma.

BACKGROUND: Glioblastoma is the most common malignant brain tumor, and thus it is important to be able to identify patients with this diagnosis for population studies. However, this can be challenging as diagnostic codes are nonspecific. The aim of this study was to create a computable phenotype (CP) for glioblastoma multiforme (GBM) from structured and unstructured data to identify patients with this condition in a large electronic health record (EHR). METHODS: We used the University of Florida (UF) Health Integrated Data Repository, a centralized clinical data warehouse that stores clinical and research data from various sources within the UF Health system, including the EHR system. We performed multiple iterations to refine the GBM-relevant diagnosis codes, procedure codes, medication codes, and keywords through manual chart review of patient data. We then evaluated the performances of various possible proposed CPs constructed from the relevant codes and keywords. RESULTS: We underwent six rounds of manual chart reviews to refine the CP elements. The final CP algorithm for identifying GBM patients was selected based on the best F1-score. Overall, the CP rule "if the patient had at least 1 relevant diagnosis code and at least 1 relevant keyword" demonstrated the highest F1-score using both structured and unstructured data. Thus, it was selected as the best-performing CP rule. CONCLUSIONS: We developed and validated a CP algorithm for identifying patients with GBM using both structured and unstructured EHR data from a large tertiary care center. The final algorithm achieved an F1-score of 0.817, indicating a high performance, which minimizes possible biases from misclassification errors.

Patterns and predictors of anxiety and depression symptom trajectories in patients diagnosed with primary brain tumors.

BACKGROUND: Patients with primary brain tumors (pPBTs) often exhibit heightened distress. This study assesses how symptoms of anxiety and depression change over time in pPBTs and identifies factors that may predict patients' symptom trajectories. METHODS: Ninety-nine adult pPBTs completed psychosocial assessments at neuro-oncology appointments over 6-18 months. Quality of life was assessed with the Functional Assessment of Cancer Therapy-Brain; symptoms of anxiety and depression were assessed with the Patient-Reported Outcomes Measurement Information System short forms. The prevalence of patients with clinically elevated symptoms and those who experienced clinically meaningful changes in symptoms throughout follow-up were examined. Linear mixed-effects models evaluated changes in symptoms over time at the group level, and latent class growth analysis (LCGA) evaluated changes in symptoms over time at the individual level. RESULTS: At enrollment, 51.5% and 32.3% of patients exhibited clinically elevated levels of anxiety and depression, respectively. Of patients with follow-up data (n = 74), 54.1% and 50% experienced clinically meaningful increases in anxiety and depression scores, respectively. There were no significant changes in anxiety or depression scores over time, but better physical, functional, and brain-cancer well-being predicted lower levels of anxiety and depression (p < 0.001). Five sub-groups of patients with distinct symptom trajectories emerged via LCGA. CONCLUSIONS: pPBTs commonly experience elevated symptoms of anxiety and depression that may fluctuate in clinically meaningful manners throughout the disease. Routine screening for elevated symptoms is needed to capture clinically meaningful changes and identify factors affecting symptoms to intervene on.

Clinical management of seizures in patients with meningiomas: Efficacy of surgical resection for seizure control and patient-tailored postoperative anti-epileptic drug management.

Meningiomas are the most common primary intracranial tumor. They are slow growing and often incidentally found tumors that arise from the arachnoid villi. As they grow, they have a greater likelihood of becoming symptomatic with seizures being one of the most clinically significant symptoms. Seizures are more likely to present as a symptom of larger meningiomas and meningiomas that compress cortical areas particularly those in non-skull base locations. These seizures are often managed medically, utilizing the same anti-seizure medications that are used to treat other causes of epilepsy. We discuss common anti-seizure medications used including valproate, phenobarbital, carbamazepine, phenytoin, lacosamide, lamotrigine, levetiracetam and topiramate and their common adverse effects. The goal of pharmacotherapy for seizure control is to maximize seizure control while minimizing the adverse effects of the medication. The decision to provide medical management is dependent on individual seizure history and plans for surgical treatment. Patients who did not require seizure prophylaxis before surgery are commonly prescribed seizure prophylaxis postoperatively. Symptomatic meningiomas not controlled by medical management alone are commonly evaluated for surgical resection. The efficacy of surgical resection in providing seizure freedom is dependent on several features of the tumor including tumor size, the extent of the peritumoral edema, the number of tumors, sinus infiltration and the degree of resection.

mRNA aggregates harness danger response for potent cancer immunotherapy.

Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of 'onion-like' multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.

Duration of Prophylactic Levetiracetam After Surgery for Brain Tumor: A Prospective Randomized Trial.

BACKGROUND: Levetiracetam is commonly used as a prophylactic antiseizure medication in patients undergoing surgical resection of brain tumors. OBJECTIVE: To quantitate side effects experienced in patients treated with 1 week vs 6 weeks of prophylactic levetiracetam using validated measures for neurotoxicity and depression. METHODS: Patients undergoing surgical resection of a supratentorial tumor with no seizure history were randomized within 48 hours of surgery to receive prophylactic levetiracetam for the duration of either 1 or 6 weeks. Patients were given oral levetiracetam extended release 1000 mg during the first part of this study. Owing to drug backorder, patients enrolled later in this study received levetiracetam 500 mg BID. The primary outcome was the change in the neurotoxicity score 6 weeks after drug initiation. The secondary outcome was seizure incidence. RESULTS: A total of 81 patients were enrolled and randomized to 1 week (40 patients) or 6 weeks (41 patients) of prophylactic levetiracetam treatment. The neurotoxicity score slightly improved in the overall cohort between baseline and reassessment. There was no significant difference between groups in neurotoxicity or depression scores. Seizure incidence was low in the entire cohort of patients with 1 patient in each arm experiencing a seizure during the follow-up period. CONCLUSION: The use of prophylactic levetiracetam did not result in significant neurotoxicity or depression when given for either 1 week or 6 weeks. The incidence of seizure after craniotomy for tumor resection is low regardless of duration of therapy.

Histologic Findings at the Time of Repeat Resection Predicts Survival in Patients with Glioblastoma.

OBJECTIVE: Radiographic worsening in patients with glioblastoma undergoing treatment may be due to tumor recurrence or treatment effect. The overall prognosis of these patients based on histologic findings at the time of repeat resection is not well established. METHODS: Patients with glioblastoma at our institution were identified. Patients who only had 1 surgery were excluded. Demographic and clinical data were recorded. The histologic diagnosis at the time of repeat surgery was recorded as either tumor recurrence or pseudoprogression. For this study, pseudoprogression was defined as absence of tumor histologic features and could show coagulative necrosis, reactive gliosis, and/or inflammatory infiltration. RESULTS: A total of 115 patients were identified, 106 with tumor recurrence and 9 with pseudoprogression. The pseudoprogression group had a greater percentage of patients with O6-methylguanine DNA-methyltransferase (MGMT) methylation (37.7% vs. 66.7%), but these results did not reach statistical significance. The overall median survival was 23.1 months. The overall median survival was 22.0 months in the tumor recurrence group and 33.3 months in the pseudoprogression group (P = 0.0814). The overall median survival from the time of repeat surgery was 8.4 months for the entire cohort, 8.3 months for the tumor recurrence group and 18.4 months for the pseudoprogression group (P = 0.0063). In multivariable analysis, presence of tumor features was predictive of worse overall survival from the time of second surgery (hazards ratio 3.96, 95% confidence interval: 1.30-12.06, P = 0.0156). CONCLUSIONS: In patients with worsening imaging, the absence of tumor on histologic diagnosis is associated with improved survival from the time of second surgery.

The trial effect in patients with glioblastoma: effect of clinical trial enrollment on overall survival.

PURPOSE: To determine whether participation in a clinical trial was associated with improved survival in patients with glioblastoma (GBM). METHODS: Following IRB approval, patients were identified using CPT and ICD codes. Data was collected using retrospective review of electronic medical records. When necessary, death data was obtained from online obituaries. Inverse propensity score matching was utilized to transform the two cohorts to comparable sets. Survival was compared using Kaplan-Meyer curves and Wilcoxon Rank Sum Test. RESULTS: In this cohort of 365 patients, 89 were enrolled in a clinical trial and 276 were not. Patients enrolled in clinical trials had a significantly higher mean baseline KPS score, higher proportion of surgical resections, and were more likely to receive temozolomide treatment than patients not enrolled in a clinical trial. After inverse propensity score matching, patients enrolled in a clinical trial lived significantly longer than those not enrolled (28.8 vs 22.2 months, p = 0.005). A potential confounder of this study is that patients not in a clinical trial had significantly fewer visits with neuro-oncologists than patients enrolled in a clinical trial (7 ± 8 vs 12 ± 9, p < 0. 0001). CONCLUSIONS: Clinical trials enroll patients with the most favorable prognostic features. Even when correcting for this bias, clinical trial enrollment is an independent predictor of increased survival regardless of treatment arm.

Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma.

Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors - cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) - and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Glioma Immunotherapy: Advances and Challenges for Spinal Cord Gliomas.

Spinal cord gliomas are rare entities that often have limited surgical options. Immunotherapy has shown promise in intracranial gliomas with some research suggesting benefit for spinal cord gliomas. A focused review of immunotherapies that have been investigated in spinal cord gliomas was performed. The primary methods of immunotherapy investigated in spinal cord gliomas include immune checkpoint inhibitors, adoptive T-cell therapies, and vaccine strategies. There are innumerable challenges that must be overcome to effectively apply immunotherapeutic strategies to the spinal cord gliomas including low incidence, few antigenic targets, the blood spinal cord barrier, the immunosuppressive tumor microenvironment and neurotoxic treatment effects. Nonetheless, research has suggested ways to overcome these challenges and treatments have been effective in case reports for metastatic non-small cell lung cancer, melanoma, midline glioma and glioblastoma. Current therapies for spinal cord gliomas are markedly limited. Further research is needed to determine if the success of immunotherapy for intracranial gliomas can be effectively applied to these unique tumors.

Role of Laser Interstitial Thermal Therapy in the Management of Primary and Metastatic Brain Tumors.

OPINION STATEMENT: Laser interstitial thermal therapy (LITT) is a minimally invasive treatment option for brain tumors including glioblastoma, other primary central nervous system (CNS) neoplasms, metastases, and radiation necrosis. LITT employs a fiber optic coupled laser delivery probe stabilized via stereotaxis to deliver thermal energy that induces coagulative necrosis in tumors to achieve effective cytoreduction. LITT complements surgical resection, radiation treatment, tumor treating fields, and systemic therapy, especially in patients who are high risk for surgical resection due to tumor location in eloquent regions or poor functional status. These factors must be balanced with the increased rate of cerebral edema post LITT compared to surgical resection. LITT has also been shown to induce transient disruption of the blood-brain barrier (BBB), especially in the peritumoral region, which allows for enhanced CNS delivery of anti-neoplastic agents, thus greatly expanding the armamentarium against brain tumors to include highly effective anti-neoplastic agents that have poor BBB penetration. In addition, hyperthermia-induced immunogenic cell death is another secondary side effect of LITT that opens up immunotherapy as an attractive adjuvant treatment for brain tumors. Numerous large studies have demonstrated the safety and efficacy of LITT against various CNS tumors and as the literature continues to grow on this novel technique so will its indications.

Inflammatory myofibroblastic tumor masquerading as an anterior choroidal artery fusiform aneurysm.

BACKGROUND: Inflammatory myofibroblastic tumor is a rare, poorly understood tumor that has been found to occur in almost every organ tissue. Its location within the central nervous system is uncommon, and patients tend to present with nonspecific symptoms. CASE DESCRIPTION: A female in her eighth decade presented to neurosurgery clinic with complaints of headache and dizziness. Initial imaging was consistent with a low-grade, benign brain lesion in the region of the left choroidal fissure. She was recommended for observation but returned 1 month later with progressive symptoms and doubling of the lesion size. She underwent surgical resection and was found to have an IMT arising from the wall of the left anterior choroidal artery. CONCLUSION: Intracranial IMT remains a rare and poorly understood entity. The present case demonstrates a novel presentation of IMT in an adult patient and exemplifies the heterogeneity of the disease presentation.

Adult precision medicine: learning from the past to enhance the future.

Despite therapeutic advances for other malignancies, gliomas remain challenging solid tumors to treat. Complete surgical resection is nearly impossible due to gliomas' diffuse infiltrative nature, and treatment is hampered by restricted access to the tumors due to limited transport across the blood-brain barrier. Recent advances in genomic studies and next-generation sequencing techniques have led to a better understanding of gliomas and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in the management of gliomas, with encouraging results in preclinical studies and early clinical trials. However, molecular characterization of gliomas revealed significant heterogeneity, which poses a challenge for targeted therapeutic approaches. In this context, leading neuro-oncology researchers and clinicians, industry innovators, and patient advocates convened at the inaugural annual Remission Summit held in Orlando, FL in February 2019 to discuss the latest advances in immunotherapy and precision medicine approaches for the treatment of adult and pediatric brain tumors and outline the unanswered questions, challenges, and opportunities that lay ahead for advancing the duration and quality of life for patients with brain tumors. Here, we provide historical context for precision medicine in other cancers, present emerging approaches for gliomas, discuss their limitations, and outline the steps necessary for future success. We focus on the advances in small molecule targeted therapy, as the use of immunotherapy as an emerging precision medicine modality for glioma treatment has recently been reviewed by our colleagues.

In situ vaccination with laser interstitial thermal therapy augments immunotherapy in malignant gliomas.

INTRODUCTION: Laser interstitial thermal therapy (LITT) remains a promising advance in the treatment of primary central nervous system malignancies. As indications for its use continue to expand, there has been growing interest in its ability to induce prolonged blood brain barrier (BBB) permeability through hyperthermia, potentially increasing the effectiveness of current therapeutics including BBB-impermeant agents and immunotherapy platforms. METHODS: In this review, we highlight the mechanism of hyperthermic BBB disruption and LITT-induced immunogenic cell death in preclinical models and humans. Additionally, we summarize ongoing clinical trials evaluating a combination approach of LITT and immunotherapy, which will likely serve as the basis for future neuro-oncologic treatment paradigms. RESULTS: There is evidence to suggest a highly immunogenic response to laser interstitial thermal therapy through activation of both the innate and adaptive immune response. These mechanisms have been shown to potentiate standard methods of oncologic care. There are only a limited number of clinical trials are ongoing to evaluate the utility of LITT in combination with immunotherapy. CONCLUSION: LITT continues to be studied as a possible technique to bridge the gap between exciting preclinical results and the limited successes seen in the field of neuro-oncology. Preliminary data suggests a substantial benefit for use of LITT as a combination therapy in several clinical trials. Further investigation is required to determine whether or not this treatment paradigm can translate into long-term durable results for primary intracranial malignancies.

Tumor Treating Fields in the Management of Patients with Malignant Gliomas.

OPINION STATEMENT: Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.