bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intra-operative desorption-electrospray ionization mass-spectrometry for real-time diagnosis, margin assessment, and maximization of brain cancer resection.
Authors: Garcia Diogo , Brown Hannah , Jentoft Mark , Middlebrooks Erik , Chaichana Kaisorn , Cooks Graham , Quinones-Hinojosa Alfredo 
Published: June 2023

2071 Background: Despite advances in our understanding of brain cancer, the ability to discern between infiltrated and non-infiltrated tissue with current adjuncts, remains elusive. Isocitrate dehydrogenase (IDH) mutation is unique to IDH-mut glioma cells and can be used as a surrogate for tumor infiltration. Further, emerging evidence has shown unique signatures in brain cancer lipidomic profiling, with lipid metabolism playing a key role in brain cancer biology. Here, we aimed to evaluate the impact of desorption electrospray ionization-mass spectrometry (DESI-MS) as a near real-time method to determine infiltration status and the use of DESI-MS to perform intra-operative histological diagnosis. Methods: This is a prospective multi-institution cohort study using intra-operative DESI-MS on freshly obtained tumor samples to evaluate 2-hydroxyglutarate (2HG), with post-hoc validation by review by a board-certified neuropathologist. For tumor cell estimation and tissue diagnosis, high-throughput DESI-MS was used for rapid analysis of high-density arrays using lipidomic profiling. Analysis of the data was performed using a pre-written algorithm employing a combination of Python- and MATLAB-based custom software allowing results in less than a second per sample. Results: A total of 496 tumor biopsies from 72 patients have been analyzed. Earlier iterations focused on absolute quantitation of 2HG in 247 biopsies from 49 patients to determine IDH genotype yielding sensitivity, specificity, and accuracy values of 89, 100, and 94% for core biopsies (71). Improvement in accuracy was obtained with relative measurement of 2HG in comparison to glutamate allowing for detection of IDH-mut infiltration at the margin, resulting in 93% sensitivity, 100% specificity, and 98% accuracy with turnover times averaging 3 minutes in 183 biopsies from 23 patients. Margin assessment beyond the limits of neuro-navigation and surgeon assessment showed tumor infiltration in 88% of margin biopsies from IDH mutant tumors (30 of 34 biopsies) with 100% accuracy. Intra-operative tissue diagnosis was pursued in 66 unique tumor samples using DESI-MS lipidomic profiling, including samples of normal brain parenchyma, gliomas, meningiomas and pituitary adenomas, split into two microarray sets (36 and 40 samples). Using estimated principal components as input features, high accuracy ( > 90%; ROC AUCs ≥ 0.89) was obtained for supervised tissue classification using simple machine learning algorithms. Conclusions: We present a novel system for intra-operative evaluation of tumor infiltration at the margin in gliomas and for intra-operative tissue diagnosis of brain cancer. Our method identified tumor infiltration beyond the surgical margins and serves as a foundation for future uses employing DESI-MS to allow for molecularly guided surgery in IDH-mut gliomas.
FOXC1 expression in meningiomas.
Authors: Wedemeyer Michelle , Xiu Joanne , Walker Phillip , Kaur Jasmeet , Davidson Christian , Ahluwalia Manmeet Singh , Sumrall Ashley Love , Zada Gabriel 
Published: June 2023

2074 Background: Meningiomas account for nearly 1/3 of brain tumors and are characterized by a low mutational burden and dysregulation of DNA methylation. The promoter of FOXC1 is hypomethylated relative to dura in meningiomas of all grades and knockdown of FOXC1 in murine models causes craniofacial hypoplasia and absent frontal dura, suggesting a role as a meningeal identity gene. Here we perform a multi-omic analysis of FOXC1 expression in a large cohort of meningiomas. Methods: A total of 555 meningiomas (148 grade I, 255 grade II and 87 grade III) were analyzed with next-generation DNA sequencing (592 gene NextSeq panel; n=150 or Agilent WES whole exome sequencing, n=405) and whole mRNA (WTS, NovaSeq, 555) at Caris Life Sciences (Phoenix, AZ). Top quartile transcripts per million (TPM) for FOXC1 expression were considered high (FOXC1-H) and bottom quartile low (FOXC1-L). Immune cell infiltration was estimated using RNA deconvolution by QuantiSeq to calculate median cell fractions (MCF) or positive percentages (PP). Data were analyzed using X2/Fisher’s-exact/Mann-Whitney U tests. A p-value<0.05 after BH correction was considered significant. Results: Median FOXC1 expression was 33 TPM. Expression of FOXC1 transcript was higher in lower grade tumors (I: 34, II: 29, III: 27, q<0.05). NF2 mutations were significantly more common in FOXC1-L than FOXC1-H tumors (45% vs. 68%, q<0.05). Although a higher percentage of FOXC1-H meningiomas harbored TERT promoter mutations (2% vs. 9%, p<0.05) and a higher percentage of FOXC1-L meningiomas harbored a TRAF7 mutation (19%. Vs. 5.5%, p<0.05), these differences were not significant after correction for multiple comparisons. Programmed cell death ligand1 (PD-L1/CD274, 2.27 vs. 492) and MHC-I (HLA-A: 58 vs. 109, HLA-B: 59 vs. 74, and HLA-C: 61 vs. 101) transcripts were more highly expressed in FOXC1-H than FOXC1-L tumors. FOXC1-L tumors exhibited significantly more B cells (MCF: 5% vs. 4%), M1 Macrophages (MCF: 2% vs. 1%), CD8+ T cells (PP: 27% vs. 7%), and a higher interferon gamma transcript signature than FOXC1-H. Infiltrates of NK cells (MCF: 3.5% vs. 4.3%) and dendritic cells (MCF: 6% vs. 8%) were higher in FOXC1-H (all q<0.05). Conclusions: The craniofacial patterning transcription factor FOXC1 was found to be widely expressed in a large cohort of meningiomas and its expression is inversely correlated with WHO tumor grade. Multi-omic analysis reveals a significant relationship between FOXC1 transcript levels and key markers of the immune environment including PD-L1 transcript expression. These data suggest that FOXC1 is a marker of meningiomas in addition to its role as a meningeal identity marker during development. Functional studies are warranted to determine whether FOXC1 is necessary for meningioma growth, whether FOXC1 plays a direct immunomodulatory role in meningiomas, and whether the lower FOXC1 expression levels in high grade tumors represent a more embryonic phenotype.
CLDN6 CAR-T cell therapy of relapsed/refractory solid tumors ± a CLDN6-encoding mRNA vaccine: Dose escalation data from the BNT211-01 phase 1 trial using an automated product.
Authors: Mackensen Andreas , Haanen John B. A. G. , Koenecke Christian , Alsdorf Winfried , Wagner-Drouet Eva Maria , Heudobler Daniel , Borchmann Peter , Bokemeyer Carsten , Klobuch Sebastian , Kutsch Nadine , Müller Fabian , Desuki Alexander , Lüke Florian , Wiegert Erol , Flemmig Carina , Schulz-Eying Catrine , Rengstl Benjamin , Preußner Liane , Türeci Özlem , Şahin Uğur 
Published: June 2023

2518 Background: We are developing a chimeric antigen receptor (CAR)-T cell therapy targeting claudin 6 (CLDN6), an oncofetal antigen that is undetectable in healthy somatic tissue and highly expressed in various solid cancers. Autologous CLDN6 CAR-T cells are being tested alone and in combination with CLDN6-encoding CAR-T cell Amplifying RNA Vaccine (CARVac), a nanoparticulate RNA vaccine designed to stimulate and expand CLDN6 CAR-T cells. Methods: The ongoing first-in-human trial BNT211-01 evaluates the safety and feasibility of CLDN6 CAR-T cell transfer ± CARVac in lymphodepleted patients with relapsed/refractory solid tumors. Patients are pre-screened for CLDN6 expression with a cut-off of 50% positivity of intermediate or strong intensity by immunohistochemistry staining. Key endpoints are safety, tolerability, and anti-tumor activity. Pharmacokinetics of adoptively transferred CAR-T cells in peripheral blood is monitored by quantitative PCR. Dose escalation proceeds according to a classical 3+3 design, testing CLDN6 CAR-T cells at each dose level as both as monotherapy and in combination with CARVac. We previously reported results from 22 patients from 4 dose escalation cohorts with a manual CAR-T production process ± CARVac (ESMO-IO LBA38) which followed the same methodology. We observed durable responses along with a manageable safety profile, in line with commercial CAR-T products used to treat B-cell malignancies. No on-target/off-tumor toxicity and only a single case of (grade 1) neurotoxicity was observed. Given the encouraging efficacy, we have implemented an automated process to scale-up manufacturing. Accordingly, we are repeating the dose escalation with an automated CAR-T cell product, and with a modified CARVac regimen. As of 1st February 2023, 7 patients with epithelial ovarian carcinoma (EOC), 4 with testicular germ cell tumors (GCT), and a further 5 patients with tumors of various indications have been infused with CAR-T cells up to DL2. We intend to submit efficacy, safety and CAR T-cell pharmacokinetics data from 5 cohorts treated with 1x106, 1x107 or 1x108 CLDN6 CAR-T cells ± CARVac with a data cut-off of March 14th, 2023 from ≥17 treated patients as a late-breaking abstract. Clinical trial information: NCT04503278 .
The immune microenvironment in hormone positive, HER2 negative breast cancer: A focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures.
Authors: Lucas Mairi , Kinsella Zak , Gonzalez Claudia Aura , Hurley Camille , O'Grady Anthony , Fay Joanna , Murphy Verena , Jahangir Chowdhury Arif , Rahman Arman , Gallagher William M. , Kelly Catherine Margaret , O'Connor Darran 
Published: June 2023

2522 Background: Hormone positive, HER 2 negative breast cancer (ER+/HER2-) has traditionally been considered an immune cold tumour subtype. Research to date indicates that TILs in ER+/HER2- breast cancer may be a negative prognostic marker. However, there is a paucity of data in this area regarding immune subpopulations and spatial phenotypes. Tertiary lymphoid structures (TLS) have been associated with improved prognosis and response to immunotherapy in other solid organ malignancies. We aim to explore the immune microenvironment in early stage ER+/HER2- breast cancer with a focus on tumour infiltrating lymphocytes, spatial phenotypes and tertiary lymphoid structures (TLS). Methods: Full face sections of archival tissue samples from patients with early stage ER+/HER2- breast cancer were stained with CD45 antibody (DAKA clone M0701) via the automated Leica Bond III system. Open source digital pathology analysis software, Qupath, was utilised to identify positive cells and calculate the percentage of positive CD45 staining cells (CD45%) within the tumour area. Spatial analysis was done to divide tumour area into three spatial phenotypes; Immune cold -lacking immune infiltrate;Immune excluded- immune cells restricted to the tumour periphery and immune hot - immune cells infiltrating the tumour core. A tissue micro array (TMA) was created and stained manually with a multiplex chromogenic immunohistochemistry panel for CD20/CD3/DCLamp to identify immune subpopulations associated with tertiary lymphoid structures. Results: A total of 409 patient samples were included in the analysis. 89% (n=367) of samples had a CD45% of 0-10%. CD45% stratification by 21-gene-recurrence score(RS) into Low, Intermediate and High showed a statistically higher CD45% in those with a High RS compared to Low RS (p value= 0.0015). We identified a trend towards worse disease free survival (DFS) in the CD45%high group which did not reach statistical significance. The immune hot spatial phenotype was associated with a worse DFS (p value = 0.034) with no statistically significant difference in DFS between immune cold and immune excluded phenotypes. The majority of samples had minimal immune infiltrate. Staining with a TLS panel revealed that samples with a significant infiltrate could broadly be divided into T cell only infiltrate or those with the presence of TLS, the significance of this is unclear. Conclusions: The majority of ER+/HER2- breast cancer samples had low numbers of TILs, however there is clear heterogeneity within this subgroup. Spatial elements and immune cell subpopulations may further guide the value of TILs in prognosis in this breast cancer subtype.
AMPLIFY-201, a first-in-human safety and efficacy trial of adjuvant ELI-002 2P immunotherapy for patients with high-relapse risk with KRAS G12D- or G12R-mutated pancreatic and colorectal cancer.
Authors: O'Reilly Eileen Mary , Wainberg Zev A. , Weekes Colin D. , Furqan Muhammad , Kasi Pashtoon Murtaza , Devoe Craig E. , Leal Alexis Diane , Chung Vincent , Perry James , Seenappa Lochana , McNeil Lisa , Welkowsky Esther , DeMuth Peter , Haqq Christopher M. , Pant Shubham 
Published: June 2023

2528 Background: RAS mutations occur in 25% of solid tumors with G12D being the most frequent variant. ELI-002 2P is a vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D and G12R mutant KRAS peptides with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Preclinical amphiphile data (relative to non-amphiphile controls) showed increased immunogenicity, tumor clearance and survival in mouse models. Methods: This first-in-human multicenter phase I trial assessed safety, immunogenicity and antitumor activity using a novel adjuvant trial design in patients (pts) with minimal residual disease (MRD) following standard locoregional treatment. Eligibility: elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker elevation (CA19-9/CEA), and KRAS/NRAS mutation. In a 3+3 dose escalation, n=22 received a subcutaneous course of 6 prime and 4 booster injections of fixed dose Amph-peptides (1.4 mg), admixed with escalating Amph-CpG-7909 (Table). Dose escalation based on observed safety in first 28 days. Safety, antitumor activity including biomarker reduction/clearance and relapse free survival using immune Response Evaluation Criteria in Solid Tumors (iRECIST) were assessed. Immunogenicity assessed by direct ex vivo Fluorospot and intracellular cytokine staining of peripheral blood mononuclear cells (T-cell responders = ≥ 2-fold increase over baseline) and by tumor CD3 immunohistochemistry in subset who underwent a biopsy. Results: No dose-limiting toxicities, treatment related SAEs or cytokine release syndrome were observed, and no maximum tolerated dose was identified. Safety: all grade 1, fatigue (19%), headache (19%), and injection site reaction (9.5%). Biomarker reduction was observed in 15/19 (79%) and in 5/5 at highest doses; clearance of MRD was observed in 4/19 (21% - n=2 pancreas, n=2 colorectal). Polyfunctional mKRAS-specific T cell responses observed in 80% of pts (n=12/15), with both CD8+ and CD4+ T cell responses for most, and CD3+ T cells observed on biopsies. The recommended phase 2 dose (RP2D) is 10.0 mg Amph-CpG-7909. Conclusions: ELI-002 2P, evaluated in a novel MRD+ trial, was safe with ctDNA and serum tumor biomarker reduction and clearance and notable immune responses. The RP2D is the start dose for a phase 1/randomized phase 2 study evaluating a new seven peptide formulation for G12 D, R, V, S, A, C, and G13D mutated solid tumors (NCT05726864). Clinical trial information: NCT04853017 . [Table: see text]
Phase Ib/IIa safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced solid tumors.
Authors: Guo Ye , Guo Jun , Cheng Ying , Wang Zhen , Li Yongsheng , Lv Dongqing , Yin Yongmei , Li Guiling , Wu Lingying , Huang Yi , Wei Shuqing , Shen Lin , Duan Huaxin , Cui Jiuwei , Luo Hong , Li Xiumin , Nan Kejun , Wang Chunyan , Luo Su-xia , Liu Ruonan 
Published: June 2023

2536 Background: PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. We had completed dose escalation from 1mg/kg to 45mg/kg and had not found DLT/MTD. In a Phase Ib dose expansion and Phase IIa studies we are evaluating the safety and preliminary anti-tumor activity of PM8002 as a monotherapy. Here, we provide an update of PM8002 Phase Ib/IIa results. Methods: During Phase Ib dose-expansion and Phase IIa studies, the majority of patients received PM8002 at 20mg/kg Q2W or 30mg/kg Q3W as a monotherapy (recommended phase II doses). The primary endpoint was ORR with secondary endpoints/objectives including safety. Results: As of Feb 3, 2023, 263 patients of advanced solid tumor with prior 0 to 4 line systematic treatment had been enrolled (1mg/kg Q2W [n=1], 10mg/kg Q2W [n =1], 20mg/kg Q2W [n=190], 20mg/kg Q3W [n=4], 30mg/kg Q2W [n=4], 30mg/kg Q3W [n=52], and 45mg/kg Q3W [n=11]). The median duration of exposure was 10.6 weeks (range, 0.1—51.0). Of the 263 enrolled patients, 211 had completed their first evaluation for efficacy. The overall ORR, regardless of tumor type, was 15.2% (32/211) with 32 PRs (20 confirmed PRs), and the DCR was 75.4% (159/211) per RECIST 1.1. Twenty-five patients with cervical cancer had an ORR of 28% (7/25). Twenty-six patients with renal cell carcinoma had an ORR of 26.9% (7/26). Twenty-six patients with platinum-resistant ovarian cancer had an ORR of 15.4% (4/26), and 27 patients with NSCLC (with EGFR mutations) had an ORR of 18.5% (5/27). Any-grade TRAEs occurred in 68.8% patients (181/263), with 18.3% Grade ≥3 (48/263). The most common TRAEs were proteinuria (17.5%), hypertriglyceridemia (11.4%), Aspartate aminotransferase (9.9%), Alanine aminotransferase increased (9.5%), Hypoalbuminemia (8.7%), and increased gamma-glutamyl transferase levels (6.8%). Thirty-six patients (13.7%) discontinued PM8002 due to TRAEs. No death-related cases occurred, and most patients remain on treatment. Conclusions: PM8002 showed encouraging antitumor activity and good safety in patients with advanced solid tumors. Phase 1b/IIa of PM8002 as a monotherapy and Phase II combination trials of PM8002 with chemotherapy are ongoing for multiple indications. Clinical trial information: ChiCTR2000040552.
A pilot study of lymphodepletion intensity for PBMC-derived, neoantigen-specific CD8+ T cells (Neo-Ts) therapy in patients with advanced solid tumors.
Authors: Li Dandan , Chen Chao , Li Jingjing , Yue Jianhui , Ding Ya , Wang Hailun , Liang Zhaoduan , Zhang Le , Qiu Si , Liu Geng , Gao Yan , Huang Ying , Li Dongli , Liu Wei , Wen Xizhi , Li Bo , Zhang Xiaoshi , Zhang Xi , Xu Rui-Hua 
Published: June 2023

2545 Background: Adoptive T cell therapy (ACT) using neoantigen-specific CD8+ T cells (Neo-Ts) derived from patient PBMC was recently developed aiming to target individual patient’s unique tumor mutations and increase treatment efficacy. But the optimal lymphodepletion intensity for Neo-T therapy has yet to be determined. Methods: In this phase I clinical trial (NCT02959905), we generated Neo-Ts from patients with locally advanced or metastatic melanoma or colon cancers that were refractory to standard therapies, and evaluated the effects of lymphodepletion at various dosages (high: 2x500 mg/m2 cyclophosphamide and 2x25 mg/ m2 fludarabine; low: 1x500 mg/m2 cyclophosphamide and 2x25 mg/ m2 fludarabine; and no lymphodepletion) during Neo-T therapy. The primary end point was safety and the secondary end point was objective response rate (ORR). Results: We showed that Neo-T therapy was safe with lymphodepletion at dosages from no lymphodepletion to high intensity. The median PFS was 7.1 months (95% CI:3.7-9.8), and median overall survival (OS) was 16.8 months (95% CI: 11.9-31.7). The ORR was 33.3% (3/9) among all groups. Three patients achieved PR, two of them were in the group without lymphodepletion. One of the PR patients refractory to prior anti-PD-1 therapy also responded to Neo-T therapy. Neoantigen specific TCRs were examined in two responding patients and showed expansion and persistence after treatment. Conclusions: Neo-T therapy with low intensity lymphodepletion or no lymphodepletion could be a safe and promising regimen for advanced solid tumors. Clinical trial information: NCT02959905 .
A phase 1 dose escalation trial of ex-vivo expanded allogeneic cord blood–derived natural killer cell immunotherapy for pediatric solid tumor malignancies.
Authors: Khazal Sajad , Gill Jonathan Benjamin , Foglesong Jessica , Yedururi Sireesha , Morani Ajaykumar , Sui Dawen , Bassett Roland L. , Gettys Suzanne , Tewari Priti , Mahadeo Kris , Gorlick Richard Greg , Shpall Elizabeth J. , Rezvani Katy , Daw Najat C. 
Published: June 2023

2546 Background: Despite aggressive multimodality therapy, survival outcomes of most patients with recurrent/refractory solid tumors remain dismal. Preclinical data have shown that natural killer (NK) cells play a significant role in controlling cancer progression, metastasis, and survival. In this phase I dose escalation trial, we evaluated the safety and phase 2 recommended dose of cord blood derived NK cells in children and young adults with recurrent/refractory pediatric solid tumors. Methods: Eligible patients were 1-40 years old. Cord blood donors were 4, 5, or 6/6 HLA matched. Ex-vivo, antigen presenting cell-mediated expansion of human cord blood derived NK cells was performed over 14 days. All patients received lymphodepleting regimen with cyclophosphamide (500 mg/m2/day) and etoposide (100 mg/m2/day) for 5 days (days -7 to -3) followed by 2 days rest and a single infusion of NK cells on Day 0. The study evaluated two dose levels using a standard 3+3 phase I trial design with an expansion cohort at the maximum tolerated dose. Results: Twelve patients (median age 16 years) received NK cells infusions. Tumor types included osteosarcoma (n = 7), Ewing sarcoma (n = 4), and synovial sarcoma (n = 1). Three patients received NK cells at dose level 1 (5 X 107/Kg), and nine patients at dose level 2 (1 X108/Kg), which was determined to be the recommended Phase 2 dose. No dose-limiting toxicities were observed. Most adverse events were grade 1 and 2 (fatigue, dizziness, nausea and vomiting). Most frequently observed grade 3 and 4 adverse events were leukopenia, neutropenia, lymphopenia, and thrombocytopenia. No cytokine release syndrome or neurotoxicity was observed. Allogeneic NK cells were detected in recipients’ peripheral blood as high as 100% of all NK cell populations and as late as 9 days post infusion. Of the 9 patients evaluable for tumor response, 3 patients (with osteosarcoma) had stable disease and 6 had progressive disease. Conclusions: Allogeneic ex-vivo expanded NK cells immunotherapy demonstrated favorable safety profile in patients with advanced pediatric solid tumors. Strategies to improve efficacy are warranted including using adjuvant therapy to increase persistence, more stringent selection strategies and gene editing approaches to increase alloreactivity against recipient tumor cells. Clinical trial information: NCT03420963 .