bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment patterns and outcomes of patients with high-grade glioma during the COVID-19 pandemic.
Authors: Chahal Manik , Aljawi Ghufran Abdulghaffar , Harrison Rebecca A. , Nichol Alan , Thiessen Brian Arthur 
Published: June 2022

e14009 Background: During the first year of the COVID-19 pandemic there was global disruption in the provision of healthcare, causing significant pressure on hospital resources. High-grade gliomas (HGG) are rapidly progressive tumors, so patients with delays in diagnosis or treatment due to COVID-19-related disruptions might have poor outcomes. Therefore, we retrospectively evaluated the impact of the COVID-19 pandemic on treatment patterns and outcomes of patients with HGG in British Columbia (BC). Methods: A case cohort with a pathologic diagnosis of HGG (grade 4 astrocytoma and glioblastoma) treated at BC Cancer centers with radiotherapy between March 1, 2020 – March 1, 2021 (“COVID era”), and a control cohort treated between March 1, 2018 – March 1, 2019 (“pre-COVID era”) were identified. Patient demographics, tumor characteristics, treatment details, and dates of radiographic progression and death were included in the chart review. Analyses were performed with one-way ANOVA and Chi-squared tests for comparisons between eras. The Kaplan-Meier method was used to assess progression-free survival (PFS) and overall survival (OS) and differences in outcome between eras were investigated using the log-rank test. Results: 164 patients were identified: 85 in the pre-COVID era and 79 in the COVID era. There was no statistically significant baseline difference in age, sex, comorbidities, ECOG, tumor diameter, IDH mutation status, or MGMT methylation status between eras. There was also no statistically significant difference between time from symptom onset to first imaging, time from first imaging to surgery, time from surgery to oncologic consultation between eras, and time from surgery to radiotherapy. Significantly more patients were managed with biopsy relative to partial or gross total resection during the COVID era 22% (17/79) than the pre-COVID era 13% (11/85) (p = 0.04). However, radiation treatment (RT) did not differ between eras, with similar rates of conventionally fractionated RT in the pre-COVID era (87%, 74/85) and the COVID era (82%, 65/79) (p = 0.23). Use of concurrent and/or adjuvant temozolomide also was not significantly different between eras (p = 0.27 and p = 0.19, respectively). Median PFS was 7.0 months in both eras (CI95 = 5.5 – 8.5 months for pre-COVID era, CI95 = 5.8 – 8.2 months for COVID era, p = 0.3), and median OS was 13 months in the pre-COVID era (CI95 = 10.3 – 15.7 months) and 16 months in the COVID era (CI95 = 11.5 – 20.5 months), though this difference was not significant (p = 0.09). Conclusions: To our knowledge, this is the first study to assess outcomes of patients treated for HGG during the COVID-19 pandemic. We found that, despite less use of surgery in the COVID era, the outcomes of patients with HGG were not affected.
Impact of next-generation sequencing (NGS) on the diagnosis of gliomas according to the WHO-2016 and WHO-2021 classification in routine clinical practice.
Authors: Diaz-Santos Javier , Cantero-Gonzalez Alexandra , Muñoz-Ayllon Marta , Garrido-Almazan Lucia , Garcia-Gonzalez Cristina , Rueda Dominguez Antonio 
Published: June 2022

e14022 Background: The WHO-2016 classification of central nervous system tumors introduced molecular data to perform the diagnosis, especially in gliomas. The cIMPACT-NOW updates and the WHO-2021 classification have consolidated this need, and today a comprehensive structured diagnosis is indicated. Therefore, we study the impact of the use of NGS in changing the diagnosis of gliomas in routine clinical practice. Methods: We have carried out a systematic search of glioma patients operated between January 2008 and September 2021 and diagnosed according to WHO-2016 and cIMPACT-NOW updated criteria at our academic medical center in Spain. All included patients were reclassified to WHO-2021 according to pathological data. Subsequently, we analyzed whether the application of NGS led to a change in the WHO-2016 or WHO-2021 diagnosis. We also analyzed the median of tumor mutation burden (TMB), variants of unknown significance (VUSs), potential enrollment eligible (PENs) and cancer-related alterations (CRAs). Results: Although our center serves a population of 1.8 million people, the scarcity of biopsied material and the difficulty of accessing NGS early enough limited the recruitable patients to 22. Of them 17 patients (77.27%) remained after NGS results with the same WHO-2016 and WHO-2021 diagnosis and in 5 (22.73%) it involved a change in diagnosis (Table). No PENs were detected for any patient. A median of 4 CRAs and 6 VUSs were detected per patient. The median TMB was 1.89 mutations per megabase. Conclusions: The scarce quality biopsied material and the limited access to NGS restrict its use in gliomas. Despite this, its impact in diagnosis cannot be ignored, in our study the diagnosis changed in 1 out of 3.18 patients regardless of the classification used. With these data we recommend increasing the effort to facilitate NGS to glioma patients early enough. Further studies remain essential to determine the impact of NGS results in treatment.[Table: see text]
Glioblastoma response to blood-brain-barrier permeable, MGMT-agnostic therapeutic LP-184 and sensitization by nucleotide-excision repair deficiency.
Authors: McDermott Joseph , Lal Bachchu , Lopez-Bertoni Hernando , Kulkarni Aditya , Zhou Jianli , Schimke Caleb , Kathad Umesh , Bhatia Kishor , Sharma Panna , Laterra John 
Published: June 2022

e14023 Background: Glioblastoma (GBM), a WHO Grade IV cancer, is the most common and most aggressive primary malignant brain tumor. Prognosis following best standard-of-care surgical resection, radiation and temozolomide (TMZ) chemotherapy is poor, with median overall survival 15-18 months. TMZ, which acts primarily by methylating DNA at O6-guanine, has marginal efficacy in ̃70% of patients due to tumor expression of O-6-methylguanine-DNA methyltransferase (MGMT) and there is no effective therapy at tumor recurrence. New treatment options are therefore desperately needed for GBM patients. LP-184 is an acylfulvene-derived prodrug that is activated by the oxidoreductase PTGR1 and primarily alkylates adenine at the N3-position. Bioinformatic analysis showed that PTGR1 is elevated in clinical GBM tumor samples compared to normal brain. LP-184 response is influenced by tumor DNA repair status, and acylfulvene-induced damage is mainly repaired by the transcription-coupled nucleotide-excision repair (TC-NER) pathway. Spironolactone, an FDA approved, blood-brain-barrier permeable diuretic, induces degradation of ERCC3 protein, a key TC-NER component. Response of NER-deficient GBM was tested through co-administration of LP-184 and spironolactone. Methods: Cell viability assays with exposure to LP-184, with and without spironolactone, were used to determine IC50 values in vitro. Subcutaneous or intracranial tumor xenograft models were used to determine tumor volume or survival differences between control and LP-184 treated mice. Results: Nanomolar concentrations of LP-184 inhibited in vitro viability of multiple GBM cell models including 4 NCI-60 GBM cell lines (mean IC50= 286 nM), the TMZ-resistant LN-18 cell line (IC50= 46 nM), M1123 GBM neurosphere line (IC50= 151 nM), and a low passage GBM neurosphere isolate (IC50= 306 nM). Co-treatment with spironolactone resulted in a 3-6 fold decrease in LP-184 IC50 values in M1123, Mayo39, and U87 cultures. Pharmacokinetic analyses in SCID mice following a single LP-184 infusion (4 mg/kg, i.v.) showed favorable CNS bioavailability with brain/plasma ratio 0.11 (Cmax= 839 nM) and brain tumor/plasma ratio 0.2 (Cmax= 2.53 µM). LP-184 (4mg/kg i.v., q.o.d X 4) induced complete regression of all pre-established s.c. U87 xenografts (N = 5) and 3 of 6 M1123 s.c. xenografts (mean tumor volumes: 1456 ± 349 mm 3 controls vs 84 ± 39 LP-184, p < 0.001) and statistically significantly prolonged survival of mice bearing pre-established orthotopic U87 and M1123 xenografts (p < 0.0001). Conclusions: These preclinical results establish LP-184 as a promising new agent for future clinical testing in patients with GBM and suggest that LP-184 may be particularly efficacious in patients with intrinsic or spironolactone-induced NER deficient tumors.
Is IDO1 an adequate target for treatment in glioblastoma?
Authors: Mariño Siancas Christian Andre , Hernandez Gonzalez Ainhoa , Domenech Marta , Esteve-Codina Anna , Arpi Oriol , Alameda Francesc , Pineda Estela , Chekhun Sviatoslav , Lopez Paradis Assumpcio , Del Barco Sonia , de la Iglesia Nuria , Gallego Rubio Oscar , Mesia Carlos , Mallo Mar , Esteve Anna , Carrato Cristina , Balana Carmen , Martínez-García María 
Published: June 2022

e14039 Background: Glioblastoma (GB) is the most prevalent primary brain tumor in adults. The first-line treatment is based on standard brain surgery and adjuvant radio-chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is a catabolic enzyme that plays a role in the metabolism of tryptophan (Trp), thereby promoting a state of immunosuppression. New treatments inhibiting this pathway are being tested in GB. This study aims to assess the expression of IDO in GB patients to determine whether this enzyme may be an actionable target for the treatment of GB. Methods: This is a retrospective transversal study whose database comes from the GLIOCAT project. Expression of IDO protein and mRNA was evaluated in tumor specimens of newly diagnosed GB patients by immunohistochemistry (IHC) (percentage of positive tumor cells) with an antibody anti-IDO1 (Sigma-Aldrich Cat#HPA027772) and by RNA sequencing (RNA-seq). RNA-seq (IIlumina HiSeq2000) in paired-end mode with a read length of 2x76bp using TruSeq SBS Kit v4). Reads were mapped to the human reference genome version hg38 with STAR. Genes were quantified with RSEM using gencode annotation version 24. Normalization of gene expression was performed with the trimmed-mean of M values (TMM) method. IDO gene expression values of -6 logCPM were considered as not expressed. Results: From the 255 samples assessed by IHC, 199 patients (78%) did not express IDO1 protein (mean 0.8±2.73, range 0-21%). From the 139 samples assessed by RNA-seq, TMM values, were negative for 49.6%, while low expression was detected for the other samples (mean -3.36 +/- 3.15 logCPM, range -6.12-4.32). Conclusions: Although IDO1 is barely expressed in normal brain tissue, certain studies show that its expression is upregulated in GB, either by tumor cells or indirectly induced in host antigen presenting cells, leading to immune evasion. Therefore, the metabolism of Trp is an attractive pathway to be targeted for the treatment of GB; however, our results show that IDO may not be the main target to be inhibited due to its undetectable or very low levels of expression.
Modelling treatment benefit for bexmarilimab (an anti-Clever-1 antibody and a novel macrophage reprogrammer) using phase I/II first-in-man trial data.
Authors: Bono Petri , Ekström Jussi , Fjällskog Marie-Louise , Jalkanen Juho , Huttunen Teppo , Koivunen Jussi 
Published: June 2022

e14500 Background: Bexmarilimab, an investigational immunotherapeutic antibody targeting Clever-1, is currently investigated in phase I/II MATINS study (NCT03733990) for advanced solid tumors. Machine learning (ML) based models combining extensive data could be generated to predict treatment responses to this first-in-class macrophage checkpoint inhibitor. Methods: 52 baseline features from 138 patients included in the part 1/2 of phase I/II MATINS trial were included in ML modelling. 19 patients were classified as benefitting from the therapy by RECIST 1.1 defined clinical benefit rate (DCR) at cycle 4. Initial feature selection was done using both domain knowledge and removal of features with several missing values resulting in 44 features from 102 patients. The remaining data was standardized and feature selection using variance analysis (ANOVA) based on F-values between response and features was performed. With this approach, and by removing features with high multicollinearity, the number of features could be further reduced, and used sample size increased by removing features with missing values, until only the most important features were included in the data. Feature selection resulted in nine baseline features from 127 patients, of which 18 with DCR, to be used for ML model selection and training Several ML models were trained, and prediction performance evaluated using leave-one-out cross-validation (LOOCV). In LOOCV a ML model is trained as many times as there are samples in the data (127 times in this case), each time leaving one sample out from the training set as a test set. Finally, the out-of-sample test results are aggregated to form an overall view of the model performance with unseen data. Regularized Extreme gradient boosting (XGBoost) was found out to be the best performing prediction model. Results: Nine baseline features were associated with bexmarilimab treatment benefit, and the best ML prediction performance was obtained with five features. CBR was associated with low TNFalpha and neutrophils, and high Eotaxin, CK, and T-regs. ML model trained with these five features performed well in LOOCV as 15/18 (83%) DCR and 101/109 (93%) non-DCR were classified correctly, and all considered classification performance metrics were excellent. In feature importance analysis, high baseline T-regs and Eotaxin, and low TNFalpha were characterized as the most important predictors for treatment benefit with relative importances of 0.34, 0.25, and 0.24 (out of 1). Conclusions: This study highlights possibility of using ML models in predicting treatment benefit for novel cancer drugs such as bexmarilimab and boost the clinical development. The findings are in line with expected novel immune activating mode-of-action of bexmarilimab. Clinical trial information: NCT03733990.
A next generation inducible armored CAR to overcome the immunosuppressive tumor microenvironment and enhances cytotoxicity of CAR-T and TILs.
Authors: Granger David , Harrasser Micaela , Evans Rachel , Muczynski Vincent , Chester Kerry , Nathwani Amit C. 
Published: June 2022

e14517 Background: The full potential of CAR-T cells in clinic is limited by the immunosuppressive tumour microenvironment (TME), which induces expression of exhaustion markers and limits the activity of tumour infiltrating lymphocytes (TILs) including CAR-T cells. We developed a next generation inducible Armored CAR platform (aCAR) that releases an anti-PD-1 checkpoint inhibitor upon CAR-T cell activation, limiting payload release exclusively to the TME, thereby reducing the risk of systemic exposure. This differentiated strategy facilitates activation of CAR-T cells and TILs within the TME and has the potential for lower toxicity. Methods: A ROR1-targeting second-generation CAR containing a 41BB-CD3ζ intracellular domain was cloned into a lentivirus transfer vector alongside a prototypic anti-PD1 antibody. The CAR was under the control of a constitutively active promoter, and the PD1 targeting payload was controlled by an inducible promoter that was activated upon engagement of CAR with ROR1 on tumour cells. CAR-T cells were subject to in vitro co-culture assays with target ROR1+ tumour cells and their cytotoxic responses evaluated by flow cytometry. Levels and binding functionality of released payload were analyzed by ELISA and flow cytometry. In vivo xenograft models were performed in NSG mice with tumor growth assessed by bioluminescent imaging (BLI) and caliper measurement of the tumour volume. Results: Non-Armored CAR cells displayed potent and specific cytotoxic responses directed towards ROR1+ TNBC and NSCLC cells lines at different effector to target (E:T) ratios. The results were equivalent or superior to CARs generated with comparator anti-ROR1 antibodies, which may be due to the ROR1 CAR targeting a membrane proximal epitope within the ROR1 frizzled domain. The aCAR cells released measurable levels of anti-PD1 payload within 5 hours of binding to ROR1 on tumors and enhanced the cytotoxic effects at challenging 1:10 E:T ratios. Established PDL1+ TNBC xenograft models using the aCAR cells and comparing with non-Armored CAR cells displayed a qualitative abrogation in tumor growth by BLI, which was confirmed and shown to be significant by caliper measurement of the tumor volume. Continuing the experiment out to 3 months showed a significant survival advantage for the animals receiving aCAR. All other cohorts were terminated by day 70, however 20% of the aCAR cohort survived at day 95. Conclusions: Our next generation inducible aCAR platform enables the release of an immune stimulating payload only in the presence of target tumor cells, enhancing the therapeutic activity of the CAR-T cells and limiting payload exposure to the site of action. This technology provided a significant survival advantage in challenging in vivo xenograft models. This coupled with its potential safety attributes merits further clinical evaluation of this approach.
Tumour ERO1A instigates T cell dysfunction by transmission of endoplasmic reticulum stress.
Authors: Liu Lihui , Li Sini , Qu Yan , Wang Jian , Fei Kailun , Wang Chao , Zhang Xue , Ma Zixiao , Bai Hua , Wang Jie 
Published: June 2022

e14533 Background: Infiltrated-excluded tumor microenvironment (TME) predicts poor prognoses in multiple malignancies. T cell dysfunction is a hallmark of immune exclusion in patients and correlates with response to immune checkpoint inhibitors (ICIs). However, strategies to classify TME based on T cell dysfunction for predicting response to ICIs are lacking. Methods: MC-38, LLC, and 4T1 tumours knocked out and restored for endoplasmic reticulum oxidoreductin-1α ( Ero1a) were engrafted subcutaneously into immunocompetent hosts. Anti-PD-1 antibody was injected intraperitoneally every three days. We used immunofluorescence staining and flow cytometry to characterize the intratumoral infiltrates. Coculturing of tumour cells with T cells, single-cell RNA-seq, and western blotting were utilized to unveil the underlying mechanisms. Multi-color immunohistochemistry was used to identify the expression of ERO1A and define TME in patient samples. Results: Here, we show that ERO1A, an oxidoreductase involved in endoplasmic reticulum stress (ER stress)-induced apoptosis, instigates an immune-exclusive TME by transmitting ER stress to T cells. In mouse models, knocking out of Ero1a in Ero1a-expressed tumours promotes the infiltration of CD8+ T cells and enhances responses to anti-PD-1 treatment. By contrast, ectopic expression of Ero1a enhances tolerance to ER stress in tumour cells by activating IRE1α-signaling. Additionally, ero1a promotes the transmission of ER stress to T cells and triggers CHOP-dependent apoptosis, resulting in an immune-exclusive TME. Elimination of ER stress status suppresses tumour growth in immunocompetent mice and promotes response to ICIs. In 37 patients with non-small cell lung cancer treated with neoadjuvant immunotherapy, the expression of ERO1A is negatively correlated with the abundance of tumour infiltrated lymphocytes ( P< 0.001) and responses to ICIs ( P< 0.001). Patients with low expression of ERO1A also exhibit a superior recurrence-free survival compared to those with high expression of ERO1A ( P= 0.039). Conclusions: Together, our findings identify a mechanism for immune-exclusive TME and suggest a potential immunotherapeutic target for terminating T cell dysfunction and apoptosis through eliminating transmissible ER stress.[Table: see text]
Preclinical anti-tumor activity of small-molecule oral PD-L1 checkpoint inhibitors.
Authors: Thi Emily P. , Cole Andrew G. , Heffernan Gavin , Iott Christina L. , Ozturk Seyma , Ganchua Sharie C. , Nguyen Dan , Graves Ingrid , Quintero Jorge G. , Stever Kim , Fan Kristi , Ahuja Vijay , Kultgen Steven G. , Shubina Maria , Liu Boya , Tang Sunny , Harasym Troy , Lam Angela M. , Sofia Michael J. 
Published: June 2022

e14558 Background: The PD-1/PD-L1 checkpoint axis is a validated target in oncology, and immunotherapy with antibody approaches have proven efficacy across various tumor types. Oral small-molecule inhibitors of PD-L1 may offer advantages over antibody approaches by enabling tunable on-target engagement and the potential for better tissue penetration and improved efficacy. Here we report the preclinical in vitro activity of small-molecule inhibitors of PD-L1 possessing a novel mechanism of action, favorable pharmacokinetics, and demonstrated in vivo efficacy in a mouse colon adenocarcinoma model. Methods: In vitro activity was assessed in a Jurkat T cell NFAT reporter assay and PD-L1 reduction was confirmed in CHO-K1 cells expressing human PD-L1 (CHO-K1-hPD-L1) and in peripheral blood mononuclear cells (PBMCs) from healthy donors. T cell activation assays were conducted with PBMCs from healthy donors. Non-specific cytokine release was evaluated in human whole blood. Pharmacokinetic (PK) evaluations were conducted in rodents and non-human primates (NHP). In vivo efficacy was evaluated in an MC38 tumor humanized PD-L1 and PD-1 mouse model. Results: Small-molecule inhibitors of PD-L1 were able to disrupt PD-1:PD-L1 and PD-L1:CD80 interactions through the reduction of PD-L1 expression on the cell surface via a novel internalization mechanism, resulting in PD-L1 degradation (EC50s ranged from 1.9 – 24 nM in CHO-K1-hPD-L1 and primary human myeloid cells). Lead PD-L1 inhibitors mediated potent activation of T cells in a NFAT reporter assay (EC50s of 13 and 18 nM) as well as dose responsive elevations in IL-2 production in human PBMCs stimulated with staphylococcal enterotoxin B. Compound treatment did not elicit non-specific cytokine release in human whole blood, supportive of favorable immune safety. PK profiles showed low systemic clearance in rodents and NHP. In an MC38 tumor model, once daily oral administration of compounds at 3, 10, and 30 mg/kg resulted in dose responsive tumor reduction that was associated with T cell activation and infiltration into tumors. Conclusions: Oral small-molecule PD-L1 inhibitors possessing a novel mechanism of action and the ability to mediate T cell activation in primary human immune cell types were identified. These compounds display in vivo anti-tumor efficacy comparable to anti-PD-L1 antibody and possess favorable preclinical profiles for further development, with the potential for all-oral treatment regimens for oncology.