Monday, September 5, 2022

OS08.7.A Lomustine and the immunocytokine L19TNF are a promising treatment combination for recurrent glioblastoma

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Abstract
Background
Treatment options for recurrent glioblastoma are limited and with the possible exception of regorafenib, no agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigated different treatment combinations based on the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and translated the most effective treatment combination to patients with recurrent glioblastoma.
Material and Methods
Orthotopic immunocompetent mouse glioma models were used to study the anti-glioma activity of L19TNF in combination with anti-PD1, bevacizumab or lomustine. Tumor growth was monitored by MRI. Flow cytometry and microscopy were used to characterize tumor-infiltrating-immune cells. MHC immunoaffinity purification and mass spectrometry were used to characterize the MHC immunopeptidome. Genetic mouse models were used to study immune-dependent effects. Subsequently, we translated the most efficient treatment combination to patients with recurrent glioblastoma within a phase I/II clinical trial (NCT04573192).
Results
The combination of L19TNF and lomustine demonstrated strong synergistic anti-tumor activity in two immunocompetent orthotopic glioma models and cured a majority of tumor-bearing mice. In contrast, combinations with anti-PD-1 or bevacizumab had only limited anti-glioma activity. Furthermore, compared to the monotherapies, the combination of L19TNF and lomustine led to the strongest increase in tumor-infiltrating lymphoid cells as demonstrated by flow cytometry and microsopy and to the highest number of peptides presented in the context of MHC-I. The treatment effect was abrograted in different genetic immunodeficient mouse models. The treatment combination of L19TNF and lomustine was well tolerated in the first patients treated within a phase I/I I clinical trial and we observed partial tumor responses also in patients with an unmethylated MGMT promoter.
Conclusion
The combination of L19TNF and lomustine demonstrated promising anti-glioma activity and patients are currently recruited within a phase I/II clinical trial for patients with recurrent glioblastoma.
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P17.11.A Experience of ketogenic diet with support of liquid formula 3:1 and high-grade gliomas: Case series

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Abstract
Background
High-grade gliomas, including glioblastoma, are the most common primary malignant brain tumors in adults. Despite the efforts to develop new therapies, treatment options remain limited and the prognosis is poor. Ketogenic diet, is an emerging complementary therapy for high-grade gliomas. It is hypothesized that through the change of the energy source from glucose to ketones and the inability of glioma cells to metabolize ketone bodies with the same ease due to inefficient oxidative phosphorylation, tumor growth is slowed. The feasibility of a ketogenic diet is a matter of concern. Its influence on the quality of life of patients with advanced cancers showing that even though it may cause constipation and reflux, quality of life is generally not affected
Material and Methods
We reported a case series of patients with high-grade gliomas using ketogenic diet with liquid formula 3:1 ratio (KDS) as a complementary treatme nt. We describe baseline characteristics, and EORTC-QLQ30 score and symptom evaluation
Results
We describe the case of 3 patients (2 women and 1 man) with diagnoses of grade 4 glioblastoma (2) and grade 3 oligodendroglioma (1), mean age 46.7 years (38- 56 years), ECOG 1 (2) and ECOG2 (1), gross tumor resection (1 glioblastoma patient), subtotal resection (1 glioblastoma patient), and biopsy (1 oligodendroglioma patient). All patients received radiotherapy, 66.7% (n=2) stupp protocol, and 33.3% (n=1) received hypofractionated therapy and adjuvant treatment with temozolomide. All patients received first line with temozolomide, and 33.3% received a total of four lines of chemotherapy. All the patients were fed orally and managed with KDS at the last progression. Median follow up time was 4 months. KDS didn't impact corporal weight and a positive impact was noted in seizure episodes (> 3 per day before vs < 3 per day after DKS) and quality of life (EORTC-QLQ30 61,3 [60 - 66,8] at the begining vs 70,9 [69,8 - 71,2] at the last visit). Regarding tolerance, one patient presented diarrhea and/or constipation grade 1 the first 5 days of treatment. Compliance was measured by days with a median adherence of 90%. Current disease status is stable disease (RANO criteria) in the three patients.
Conclusion
KDS could be an interesting therapy complementary to standard treatment in patients with high grade gliomas, especially in those patients who debut with seizures, improving quality of life and number of convulsive crises. More studies in adult patients are required to confirm this hypothesis
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P17.09.A Regorafenib and Re-irradiation: analysis of clinical outcomes and toxicities in patients with recurrent glioblastomas

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Abstract
Background
Glioblastoma is the most common and aggressive primary brain tumor in adults.The aggressiveness and poor prognosis related to this disease join to the limited available treatment options. The current standard of care involves surgical resection followed by concomitant radiotherapy and chemotherapy. At recurrence, no standard treatment exists and there are no guidelines to facilitate decisions in the recurrent setting. Available options include re-operation, re-irradiation, systemic therapy, alone or in combination. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. Regorafenib (Stivarga) is an inhibitor of several kinases involved in the mechanisms that regulate neoangiogenesis processes, through the inhibition vascular endothelial growth factor (VEGF) receptors and the modifications of the tumor microenvironment; specifically, Regorafenib binds an d stabilizes PSAT1 (phosphoserine aminotransferase 1). The dual regulatory mechanism underlying PSAT1-induced autophagy arrest accounts for the superior anti-GBM effect of Regorafenib compared with Temozolomide.
Material and Methods
15 patients with documented disease progression after surgery followed by RT and TMZ were assigned to receive regorafenib (REG) 160 mg once daily for the first 3 weeks of each 4-week cycle. All patients received prior radiation therapy (RT) to a median dose of 60 Gy (range 40.05 -60). Median time to retreatment after prior RT was 16 months (range 14-33). Tumor volumes ranged from 81.7 cm3 to 422.4 cm3 (CTV) and from 112.7 cm3 to 422.4 cm3 (PTV).3 patients (20%) received concomitant reirradiation with a radiation dose of 37.5 Gy in 15 fractions of 2.5 Gy.
Results
the median follow-up was 9.5 months (range 5-22). The overall survival and the progression-free survival rates were 53,8 %, and 46,6 % respectively at 2 years. In 53% the sympto ms were stable. Only one patient developed late toxicity: acute pancreatitis (Grade I) regressed on interruption of Regorafenib. No other neurological deficits occurred during follow-up. At last follow up 60% of patients were alive.
Conclusion
we report our experience with Regorafenib, administered in patients with rapid progression after the end of postoperative radio chemotherapy treatment. Regorafenib might be a new potential treatment option for recurrent glioblastoma: it was well tolerated also in cases of combined treatment with reirradiation and appeared effective. Other studies will be necessary to evaluate and confirm the role of Regorafenib in glioblastoma patients and the potential effectiveness of the combined therapeutic strategy: Regorafenib-reirradiation.
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PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma?

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Abstract
Background
Recently, 'don't eat me'-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MdM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM.
Material and Methods
We employed a CT-2A orthotopic GBM mouse model with MG specific (Sall1CreERT2 x Sigleceflox) and whole innate-compartment (Cx3cr1CreERT2 x Sigleceflox) spatio-temporal deletion of Siglece. We applied multi-color flow cytometry, transcriptomics and proteomics analysis to decipher the immune response upon Siglece knockout.
Results
TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). In the MG specific spatio-temporal deletion of Siglece (Sall1CreERT2 xSigleceflox), we observed high MG-proliferation upon Siglec-E knockout (Ki-67+ MG 1 4.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). By extending the Siglece knockout to the MdM compartment in our glioma mouse model (Cx3cr1CreERT2 x Sigleceflox) we observed a significantly prolonged survival in the Cx3cr1Cre+ population (21d in Cre- vs. 27d post-tumor injection in Cre+, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (30d post-tumor injection in Cre+ + anti-CD47). Unbiased proteomics analysis revealed increased antigen processing and presentation capabilities of Siglece knockout MdMs which was confirmed by ex-vivo OT-1 cross-presentation assays. This bridging of innate and adaptive responses with increased T cell priming upon MdM Siglece knockout was further promoted by addition of anti-PD1 antibody to the combined Siglece knockout and anti-CD47 treatment arm. Animals harboring CT-2A tumors, exhibited a sustained survival benefit under the triple therapy, with 23% of animals experiencing long-term remission, even after tumor re-challenge into the contra-lateral hemisphere. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with increased GBM-cell phagocytosis by MG and MdMs and less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003).
Conclusion
These data identify the sialic-acid-Sigl ec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
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P10.10.A Tumor Treating Fields (TTFields), temozolomide and lomustine co-application is efficacious in glioblastoma cancer cell lines

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Abstract
Background
Temozolomide (TMZ) is the standard of care chemotherapy for newly diagnosed glioblastoma (ndGBM), the most common primary malignant brain tumor in adults. However, 50% of patients do not respond to TMZ due to expression of O6-methylguanine-DNA methyltransferase (MGMT), the enzyme involved in repair of TMZ-induced damage. Tumor Treating Fields (TTFields) are alternating electric fields that display anti-mitotic effects on cancerous cells, and have been shown to induce a state of BRCAness in various cancer types. Concurrent treatment with TMZ and TTFields demonstrated a major advance in treatment of patients with ndGBM, and was approved by the FDA in 2014. Recently, the addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in ndGBM patients, with improved overall and progression free survival. The aim of the current study was to examine in GBM cells the effect of TTFields in conjunction with TMZ and CCNU.
Materi als and Methods
U-87 MG, LN229, U118 and LN18 human GBM cell lines were tested for their MGMT expression levels, and treated with TTFields (200 kHz, of 0.83 V/cm RMS) for 72 h using the inovitro system. Efficacy of concomitant application of TTFields with TMZ and/or CCNU was tested by measuring cell count, colony formation, and apoptosis levels.
Results
U-87 MG and LN229 displayed no expression of MGMT, while U118 and LN18 expressed low and high levels of MGMT, respectively. Application of TMZ and TTFields resulted in increased cytotoxicity compared with each treatment alone, with an additive interaction seen in all examined cell lines. The cytotoxic effect resulting from co-application of CCNU with TTFields suggested a synergistic interaction between the two modalities for U-87 MG, LN229, and U118, an additivity for LN18. Concurrent TTFields/TMZ/CCNU was more efficacious than TTFields or TMZ/CCNU separately in all cell lines.
Conclusions
Application of TTFiel ds with TMZ was additive, irrespective of MGMT expression levels, while TTFields with CCNU was additive when MGMT was plentiful, but displayed tendency to synergism when MGMT was absent or limited. These outcomes are in line with the BRCAness state induced by TTFields, as in the absence of MGMT, DNA damage induced by CCNU requires the BRCA pathway for repair. Application of TTFields together with TMZ and CCNU demonstrated increased efficacy, suggesting potential benefit of such therapy for ndGBM treatment.
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P17.15.A Neoadjuvant immunotherapy in the treatment of recurrent glioblastoma: an overview of last decade

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Recurrent glioblastoma (ArGB) is one of the most common primary malignant brain tumors in adults, with a poor prognosis, with low patient survival even after treatment. Because of this, several studies were carried out evaluating different therapies for the treatment of ArGB, more recently studies have emerged regarding the use of neoadjuvant immunotherapy and its possible advantages in the treatment of such patients. Therefore, the present study aims to analyze the efficacy of neoadjuvant immunotherapy and its effect on the survival of patients with recurrent glioblastoma.
Material and Methods
A search was performed in PubMed, Embase and Cochrane databases using the keywords: "Immunotherapy, "neoadjuvant" and "recurrent glioblastoma". Articles from the last 10 years were selected and those that did not meet the inclusion criteria were excluded from the research, totaling 7 selected articles.
Results
P atients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy after surgery, had significantly prolonged survival compared to patients who were randomized to receive adjuvant post-surgical PD-1 blockade alone. Neoadjuvant PD-1 blockade was associated with up-regulation of T cells and interferon-γ-related gene expression, but with down-regulation of cell cycle-related gene expression within the tumor, which was not observed in patients receiving adjuvant therapy. isolated.
Conclusion
Neoadjuvant immunotherapy, through a PD-1 inhibitor, in patients with ArGB, results in positive biological effects, in addition to the clinical benefit of, on average, increasing overall survival considerably due in large part to the improvement of the immune response , with no noticeable adverse effects, thus being advantageous, although these results are early and the current studies are not very comprehensive. Larger studies are needed for greater reliabil ity and statistical relevance.
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P17.03.B Modelling migration of glioblastoma patient-derived cells using human iPSC-derived neural spheroid and high content analysis

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour in adults. Despite current advances, the existing standard of treatment is ineffective, and the survival prognosis remains just over a year from diagnosis. Migrating tumour cells have been implicated in the therapeutic resistance of GBM. They spread by interacting with structures such as white matter tracts and inevitably cause recurrence of the tumour. Valuable cell models able to capture the invasiveness of GBM are critically needed to develop innovative therapies targeting migrating GBM cells.
Material and Methods
We established an in vitro model mimicking the GBM microenvironment by co-culturing patient-derived GBM cells and human induced pluripotent stem cell-derived cortical neural spheroids with radiating axons. Using high content imaging, we developed a robust workflow to quantify the GBM cells infiltration of the neural spheroid in endpoint assays. Images were acquired on the Operetta CLS high content device (Perkin Elmer) and analysed using the built-in Harmony Imaging and Analysis Software. We also performed live imaging assays using the Livecyte quantitative phase imager (Phasefocus), in which we studied the directionality, displacement and speed of the GBM cells engaged on axons.
Results
Our data indicate that GBM cells change morphology when cultured on axons and that they migrated towards the neural spheroid once engaged on axons. We showed that cell lines from different patients vary in migratory properties as well as in levels of infiltration capability. Finally, we used this model to test several antagonists to pathways involved in migration of GBM cells.
Conclusion
The main deliverable of this project is the setup of a novel model able to mimic the GBM migration on axons and able to screen for compounds affecting cell migration. This could pot entially offer innovative precision-medicine therapies.
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KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
In glioma patients, multimodal therapy and recurrent tumor result in local brain tissue changes, characterized by pathologic findings in structural MRI and metabolic PET images. Little is known about these different lesion types' impact on the local white matter fiber architecture and clinical outcome.
Patients and Methods
This study included data from 121 pretreated patients (median age, 52 years; ECOG, 01) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median time of 14 months (range, 1-214 months), post-therapeutic structural and metabolic findings were evaluated using anatomical MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET acquired on a 3T hybrid PET/MR scanner. Local fiber densi ty was estimated from tractography based on highangular resolution diffusion-weighted imaging. A cohort of 121 healthy subjects selected from the 1000BRAINS study and matched for age, gender and education served as a control group.
Results
The median volume of resection cavities, contrast-enhancing regions, regions with pathologically increased FET uptake, and T2/FLAIR hyperintense regions amounted to 20.9, 7.9, 30.3, and 53.4 mL, respectively. Compared to the control group, the average local fiber density in these regions was significantly reduced (p<0.001). Resection cavities showed the highest reduction, followed by contrast-enhancing lesions and metabolically active tumors on FET PET (relative fiber density reduction, -87%, -65%, -55%, respectively). The local fiber density was inversely related (p=0.005) to the FET uptake in recurrent tumors. T2/FLAIR hyperintense lesions, either assigned to peritumoral edema in recurrent glioma or radiation-induced gliosis, had a c omparable impact on reducing fiber density (48% and 41%, respectively). The total fiber loss (average fiber loss multiplied by lesion volume) associated with contrast-enhancing lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on the general performance status of the patients (ECOG score).
Conclusions
Our results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients' performance due to the larger volume affected.
Funding
Funded by the 1000BRAINS study (INM, Research Centre Juelich, Germany), Horizon 2020 (Grant No. 945539 (HBP SGA3; SC)), and Heinz Nixdorf Foundation.
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Antiretroviral drug–drug interactions: A comparison of online drug interaction databases

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Antiretroviral drug–drug interactions: A comparison of online drug interaction databases

Actual or Potential Drug–drug Interactions Identified.


Abstract

What is known and objective

Antiretrovirals have a high drug interaction potential, which can lead to increased toxicity and/or decreased efficacy. Multiple databases are available to assess drug–drug interactions. The aim of our study was to compare interaction identification for commonly used ARVs and concomitant medications between six different online drug–drug interaction databases.

Comment

This was a cross-sectional review using each of the following six databases: LexiComp®, Clinical Pharmacology®, Micromedex®, Epocrates®, University of Liverpool, and University of Toronto. Sixteen antiretroviral drugs and 100 of the DrugStats Database "Top 200 of 2019" list of medications were included. Each of the six databases identified a different number of actual or potential interactions. The number of interactions ranged from 211 to 283.

What is new and conclusions

A variety of databases exist with inconsistent identification of actual or potential drug–drug interactions amongst them. It may be beneficial to cross-reference multiple databases prior to making decisions regarding patient care.
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Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial

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Abstract
Background
Despite vaccination, many remain vulnerable to COVID-19 and its complications. Oral antivirals to prevent COVID-19 progression are vital. Based upon perceived potency and clinical efficacy, favipiravir is widely used to treat COVID-19. Evidence from large randomized controlled trials (RCT) is lacking.
Methods
In this multicenter double-blinded placebo-controlled RCT, adults with early mild-to-moderate COVID-19 were 1:1 randomized to favipiravir or placebo. The study evaluated time to sustained clinical recovery (TT-SCR), COVID-19 progression, and cessation of viral shedding.
Results
Of 1187 analyzed patients across 40 centers, 83.3% were Hispanic, 89.0% unvaccinated, 70.3% SARS-CoV-2 seronegative, and 77.8% had risk factors for COVID-19 progression. The median time from symptom presentation and from positive test to randomization was three and two days, respectively. There was no difference in TT-SCR (median of 7 days for both groups; p = 0.80), COVID-19 progression [11 patients each (1.9% vs. 1.8%); p = 0.96], time to undetectable virus [median = 6 days, 95% CI (6-8) vs. 7 days, 95% CI (6-9)], or in undetectable virus by end of therapy (73.4% vs. 72.3%; p = 0.94). Outcomes were consistent across the analyzed sub-groups. Adverse events were observed in 13.8% and 14.8% of favipiravir-treated and placebo-treated subjects, respectively. Uric acid elevation was more frequent among favipiravir-treated subjects (19.9% vs. 2.8%).
Conclusions
Favipiravir was well tolerated but lacked efficacy in TT-SCR, progression to severe COVID-19, or cessation of viral shedding and should not be used to treat patients with COVID-19.
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