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.
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.
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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.
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.
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.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants, specifically in brain tumor patients, but they are widely used for venous thromboembolism in this population. A group of neuro‐oncology experts convened to provide practical clinical guidance for the off‐label use of direct oral anticoagulants in treating venous thromboembolism in patients with brain tumors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BackgroundTTFields induce anti-tumor immunity via simultaneous activation of type-1 interferon (T1IFN) pathways of the STING and AIM2 inflammasomes and immunogenic cell death.1 Thus, TTFields-treated ...GBM cells may provide a complete in situ vaccination platform and synergize with immune checkpoint inhibitors to prolong survival in GBM patients.MethodsWe enrolled 26 newly diagnosed GBM patients in a pilot phase 2 study combining TTFields, pembrolizumab and maintenance temozolomide (TMZ). To distinguish immune effects of TTFields from those of pembrolizumab, TTFields was started at cycle 1 of TMZ while pembrolizumab (200 mg IV every 3 weeks) at cycle 2 of TMZ. Primary endpoints were progression-free survival (PFS) versus case-matched controls treated with TTFields plus TMZ only in the EF-14 study.2 Secondary endpoints included overall survival (OS), toxicity, signature and mechanism of response by multiomics analyses of PBMCs and tumors.ResultsThe median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. Median PFS was 12.0 months versus 5.8 months in a case-matched control cohort of 26 patients (HR = 0.377; 95% CI: 0.217–0.653; P = 0.0026). Median OS was 24.8 months versus 14.6 months in controls (HR = 0.522; 95% CI: 0.301–0.905; P = 0.047). Importantly, residual tumor size positively correlated with the objective response and survival. Six of 15 (40%) patients with measurable disease achieved partial to complete response. The most common serious adverse events were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (7.7%) patients, respectively. Molecular analyses prior to the addition of pembrolizumab confirmed robust T cell activation by TTFields via the T1IFN trajectory, as evidenced by a high correlation between TCRab clonal expansion and T1IFN responsive plasmacytoid dendritic cells (Spearman coefficient = -0.8; P = 0.014) and defined a T cell-based gene signature of TTFields effects. Subsequently, the ability of the top expanded TCRab clones to adapt to the everchanging tumor microenvironment through successful clonal switching by 2 months after the addition of pembrolizumab strongly predicted response to the triple combination in a Cox HR fit model for OS with a concordance rate of 0.876, P = 0.031.ConclusionsThe triple combination was well tolerated and demonstrated promising efficacy in ndGBM. Bulky residual disease was associated with better outcomes, consistent with the in-situ immunizing properties of TTFields, which synergize with pembrolizumab. Additional molecular analysis will be updated.ReferencesChen D, Le SB, Hutchinson TE, et al. Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma. J Clin Invest 2022;132Stupp, R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA, 201; 318(23): 2306−2316.Ethics ApprovalThe study was approved by USC’s and UF’s IRBs, approval numbers USC#HS-23–00020 and UF#IRB201702270, respectively.
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).
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.
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.
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.
Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create “onion-like” multi-lamellar RNA lipid particle aggregates (LPAs) to ...substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became “hot” within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
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•RNA-LPAs mimic dangerous emboli for lymphoreticular entrapment and systemic immunity•Systemic immunity resets both the peripheral and intratumoral milieu via IFNAR1/RIG-I•RNA-LPAs are safe and effective tumor re-modulators in canines with spontaneous gliomas•RNA-LPAs reprogram the TME and elicit adaptive immunity in human GBM patients
Systemically administered mRNA aggregates (RNA-LPA) transfect lymphoreticular organs, inducing a massive cytokine/chemokine response that rapidly reprograms the tumor microenvironment while mobilizing dendritic cells/lymphocytes to elicit rapid and enduring cancer immunotherapy.
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