bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global, national, and regional burden of brain and central nervous system cancer in youth under 20 from 1990-2019: A benchmarking analysis.
Authors: Vemparala Priyatha , Lakkimsetti Mohit , Patel Dhruval Pinalkumar , Singh Kushagrita , Goel Shrey , Reyaz Ibrahim , Bathvar Pinank , Savaliya Prashantkumar , Ahmed Danish , Sharafeldin Mohammed Yassmeen , Sonani Shivani B , Patel Juhi , Koyani Himanshu Bharatkumar , Amin Vishrant , Gadhiya Dhruvkumar , Desai Hardik Dineshbhai 
Published: June 2024

2084 Background: Brain and central nervous system (CNS) cancer ranks as the second leading cause of death among all cancer-related fatalities globally in individuals under 20 years old. Despite its significance, there is a notable dearth of data on brain and CNS cancer in this age group, necessitating a comprehensive cross-country comparison. Methods: Utilizing the Global Burden of Disease study framework, we estimated the prevalence, incidence, deaths, and disability-adjusted life years (DALYs) attributable to brain and CNS cancer by age, sex, year, and location across 204 countries and territories from 1990-2019. Results: The total prevalence increased from 153,334 (95%UI: 111,452-233,819) in 1990 to 212,459 (164,908-245,556) in 2019, with incidence rising from 47,373 (32,635-74,710) in 1990 to 47,600 (36,572-55,194) in 2019. Notably, the annual percentage change (APC) in deaths decreased by 21% (56-15), and DALYs by 22% (57-15) from 1990-2019. Sub-Saharan Africa and the African Union exhibited the highest APC increase in deaths, while Southeast Asia, East Asia, and Oceania experienced the most significant decrease. The highest APC in incidence occurred in the 10-14 years age group at 27%, with a slight increase of 1% in deaths observed in the 10-19 years age group. Females bore a higher burden compared to males, with APC in prevalence at 29% versus 51%, and incidence at -4% versus 7%. Conclusions: Brain and CNS cancer accounted for 9.55% of deaths among individuals under 20 globally in 2019. While the overall global trend has shown an increase over the last three decades, females exhibit a higher burden. Despite a decrease in deaths over the same period, strategies must be implemented to combat this burden, emphasizing the importance of early investigation and management, particularly in resource-limited settings worldwide. [Table: see text]
Emavusertib (CA-4948) in combination with ibrutinib in patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL).
Authors: Grommes Christian , Tun Han W. , de la Fuente Burguera Adolfo , Dabrowska-Iwanicka Anna , Regales Lucia , Zhao Wanying , Ferrari Dora , Fowles Meaghan , Lane Maureen E , Wang Catherine , Von Roemeling Reinhard W. , Taszner Michal , D'angelo Christopher , Nowakowski Grzegorz S. 
Published: June 2024

2087 Background: PCNSL is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial rates of responses to HD-MTX-based induction chemotherapies, most patients relapse in two years. R/R PCNSL is associated with poor prognosis, representing a clear unmet medical need, as there are no currently approved treatments for this disease. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4 and FLT3, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with ibrutinib overcomes resistance to BTK inhibitors. This combination has an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Here we present updated safety and efficacy data for emavusertib in combination with ibrutinib in patients with R/R PCNSL. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) in a 21-day cycle until tumor progression or unacceptable toxicity. Results: Here, we present updated data from R/R PCNSL patients with prior ibrutinib exposure who were treated with emavusertib in combination with ibrutinib. The median number of prior lines of anti-cancer therapies was 3 (range: 2-5), all patients were R/R to both frontline therapy and subsequent ibrutinib regimens. Prior responses to ibrutinib based regimens included only 1 CR. Here, we report a higher CR rate when these patients are subsequently treated with emavusertib in combination with ibrutinib.Results revealed no dose-limiting toxicities. Conclusions: Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous exposure to ibrutinib (BTKi). Enrollment in this trial is ongoing (NCT03328078). Clinical trial information: NCT03328078 .
Use of IL-3RB to mediate antitumor effect of CAR-T cells through the JAK-STAT signaling pathway.
Authors: Ma Qizhi , Shu Pei , Guo Fuchun , Liu Ning , Bai Yongmei , Zhang Benxia , Chen Yue , Wang Yongsheng 
Published: June 2024

2541 Background: The application of CAR-T in solid tumors has not yet demonstrated significant clinical benefits. The continuous proliferation and decreased terminal differentiation of CAR-T cells in vivo are considered potential strategies that could alter this predicament. Cytokines, as the 3rd signal for T-cell activation, play a crucial role in the lifecycle and fate of T cells. In this study, we innovatively incorporated the IL-3 receptor β chain (IL-3RB) into the CAR structure to enhance signal transduction, potentially activating the anti-tumor function of CAR-T and maintaining the persistent proliferative activity. Methods: Transcriptional profiling analysis performed on HER2 or VEGFR1 CAR-T cells, with a specific focus on the gp140 cytokine family (IL-3/IL-5/CSF-2) and the receptor expression, validated by ELISA and Western blot. By cloning CAR genes containing different structural domains of the IL-3RB into the lentiviral vector pWPXLd, CAR expression, activation, depletion, proliferation, cytotoxicity, pSTAT3 and pSTAT5, and cytokine release of CAR-T cells were assessed using flow cytometry (FCM), Western blot (WB), RTCA, CCK-8, and ELISA. Subcutaneous/abdominal injections of SKOV3 cells or SKOV3-Luc cells into NSG mice, followed treated by CAR-T cells. Tumor burden was regularly monitored, and FCM and Q-PCR were utilized to assess the quantity and phenotype of CAR-T cells in vivo. Results: RNA-sequence, ELISA and WB revealed that upon activation of CAR-T cells, the expression of genes such as IL-3/IL-5/CSF-2 rapidly increased. However, their receptors were hardly expressed. IL-3RB modification did not affect the phenotype of resting CAR-T cells. But, co-cultured with target cells, IL-3RB significantly enhanced the anti-tumor effects of CAR-T cells. This was manifested by more rapid activation, promotion of persistent proliferation, delayed exhaustion phenotype, secretion of higher levels of cytokines (IL-2, IFN-γ, TNF-α) and efficient cytotoxicity. IL-3RB-expressing CAR-T cells exhibited activation of the JAK kinase and STAT3, STAT5 transcription factor signaling pathways in vitro. We established solid tumor models of subcutaneous (SKOV3) and intraperitoneal metastasis, where HER2/VEGFR1 CAR-T cells partially inhibited tumor cell growth in vivo. In contrast, IL-3RB-enhanced CAR-T cells completely eradicated tumor cells, and even achieving a state of complete remission. FCM and Q-PCR also confirmed that IL-3RB significantly improved the proliferation and survival of CAR-T cells in vivo. Conclusions: IL-3RB is scarcely expressed in T cells and not regulated by T cell activation. IL-3RB-modified CAR-T cells exhibit superior persistence and significant anti-tumor advantages in a solid tumor through the JAK-STAT signaling pathway. Our innovative CAR structure design has the potential to demonstrate promising anti-tumor effects in clinical translational applications.
The role of obesity on outcomes of adoptive cellular therapy in solid tumors.
Authors: Tao Derrick Law , Nardo Mirella , Leung Cheuk Hong , Lin Heather Y. , Kang Lei , Le Hung , Dumbrava Ecaterina Elena , Hong David S. 
Published: June 2024

2544 Background: Anti-tumor response and toxicity outcomes with adoptive cell therapy (ACT) have been heterogeneous in solid tumors, and it is still unclear how host factors such as obesity may contribute to efficacy and immune-related safety events. Methods: We conducted a retrospective study including 95 consecutive advanced solid tumor patients who received ACT on protocol in the Department of Investigational Cancer Therapeutics between August 2017 and June 2023. We analyzed baseline clinical characteristics, immune-related safety events, response to ACT, and survival outcomes between obese and non-obese patients. Overweight was defined as body mass index (BMI) 25-29.99 kg/m2 and obesity was defined as BMI ≥ 30 kg/m2 at the time of treatment. Fisher’s exact test was used to compare the proportions of categorical variables between two groups. Pairwise comparison with Bonferroni correction was performed if necessary. T-test was used to compare the mean of continuous variables between two groups. The distributions of overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method. Log-rank test was used to compare the distributions of OS and PFS by baseline characteristics. Hazard ratio was estimated in Cox proportional hazard regression model. A two-sided p-value < 0.05 was considered statistically significant. Results: The median age at treatment was 60.9 (range 20.5 – 84). Thirty-nine patients (41.1%) had a BMI (kg/m2) defined as normal weight, 26 (27.4%) as overweight, 27 (28.4%) as obese, and 3 (3.2%) as underweight. Eighty-four (88.4%) were Caucasian; 54 (56.8%) were female. The most prevalent cancers were gastrointestinal (21.1%), gynecologic (15.8%), sarcoma (11.6%), mesothelioma (10.5%), breast (8.4%). The median follow-up was 39.9 months, with a median PFS of 2.8 months (95% CI: 2.3, 3.5) and a median OS of 8.4 months (95% CI: 6.4, 11.0). The risk of death among the obese patients was 0.56 (95% CI: 0.31, 0.99) times the risk of death among normal weight patients (p = 0.045). No weight difference was found between responder and non-responder. While BMI was not associated with the development of cytokine release syndrome (CRS), the patients with normal weight had a higher proportion of immune effector cell-associated neurotoxicity syndrome (ICANS) than the obese patients (23.1% vs 0%, p = 0.049). Conclusions: Obesity was associated with improved survival and decreased ICANS rates following ACT. Our findings may suggest a differential interaction between obesity, different immunotherapeutic modalities, and hematologic vs nonhematologic cancers.
Effect of placental circulating T cells expressing CD16 on multiple hematological and solid tumor cancers through combination with various monoclonal antibodies.
Authors: Karasiewicz-Mendez Kathy , Tess Kristina , Djedaini Mansour , Huang Chenfei , Gleason Joseph , Lin Shengchen , Ruggeri Barbaro Natalia , Fitzgerald John , He Shuyang , Hariri Robert , Kilcoyne Adrian 
Published: June 2024

2554 Background: PT-CD16VS is an allogeneic cell therapy derived from human postpartum placental circulating T (PT) cells that are genetically modified to express CD16 and endogenous T cell receptor (TCR) knockout. PT-CD16VS cells can be combined with various monoclonal antibodies to engage in anti-tumor antibody-dependent cellular cytotoxicity (ADCC) against diverse cancers with a “universal receptor” approach. Here we report the characterization and preclinical evaluation of PT-CD16VS in combination with monoclonal antibodies against both hematological and solid tumor cancers. Methods: PT cells were activated, transduced with a lentiviral vector containing a construct expressing a high affinity CD16 variant, CD16VS, and transfected to knock out the TCR. In vitro,functional activity of PT-CD16VS cells in combination with monoclonal antibodies was assessed in cytotoxicity, cytokine release, and proliferation assays. Invivo, PT-CD16VS was combined with Rituximab in a Raji xenograft model in NSG mice, and with Trastuzumab in a subcutaneous NCI-N87 xenograft model in NSG mice in which tumor volume was measured and tumor samples were evaluated for PT-CD16VS infiltration. Results: In vitro, PT-CD16VS exhibited potent ADCC and cytokine release when combined with Rituximab against CD20+ Burkitt's lymphoma (Daudi and Raji), with Trastuzumab against HER2+ gastric carcinoma (NCI-N87), with Trastuzumab or Avelumab against HER2+/PDL-1+ non-small cell lung carcinoma (NCI-H1975) and Trastuzumab-resistant metastatic mammary adenocarcinoma (JIMT-1), and with Cetuximab against EGFR+ triple negative metastatic mammary adenocarcinoma (MDA-MB-231). Moreover, examples of PT-CD16VS antigen-specific proliferation were demonstrated against Raji and NCI-N87 when cells were combined with Rituximab and Trastuzumab, respectively. In vivo, in combination with Rituximab in the Raji mouse model, PT-CD16VS exhibited significant survival benefit compared to vehicle and Rituximab alone treated groups. In the subcutaneous NCI-N87 solid tumor model, PT-CD16VS with Trastuzumab demonstrated significant reduction in tumor volume compared to vehicle, Trastuzumab, and Enhertu groups. In addition, PT-CD16VS infiltration into the tumor was shown to be Trastuzumab dependent, with infiltrating cells expressing high levels of CD16 and Ki67. Conclusions: Our results show that PT-CD16VS have potent in vitro and in vivo ADCC activity, and a single drug product has the potential to be combined with various monoclonal antibodies to target multiple cancers across hematological and solid tumor indications. This “universal receptor” with antibody-dependent targeting approach, together with the benefits of an allogeneic cell platform, may democratize accessibility of such therapies for patients.
Chimeric antigen receptor T-cell therapy in B-cell malignancies and DNA-methylation–based biological aging.
Authors: Nannini Drew Robert , Cortese Rene , Hildebrandt Gerhard 
Published: June 2024

2562 Background: Chimeric antigen receptor T-cell (CAR T-cell) therapy, a type of cancer immunotherapy which leverages genetically altered T cells to target cancer cells, has shown to be an effective option for patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). Despite its growing use, the effect of CAR T-cell therapy on the aging process remains limited and findings may have implications for disease relapse and age-related diseases among survivors. The purpose of this study was to investigate the association between CAR T-cell therapy and markers of biological aging. Methods: DNA methylation and clinical data from a publicly available dataset (GSE179414) were used in this analysis. Transduced and untransduced T cells from patients with ALL (n=77) and NHL (n=37) underwent DNA methylation profiling using the Illumina Infinium MethylationEPIC BeadChip. Six DNA methylation-based biological age metrics were calculated: intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), telomere length attrition (TLA), and DunedinPACE (Pace of Aging Calculated from the Epigenome). Multiple linear regression analyses were performed to examine the association between CAR T-cell therapy and the aging metrics by B-cell malignancy. Interaction and stratified analyses by chronological age was additionally performed. Results: DunedinPACE ( P=0.002) was positively associated with CAR T-cell therapy among patients with ALL with an approximately 1-month higher pace of aging in transduced T cells compared to untransduced T cells after adjusting for chronological age and sex. Moreover, chronological age significantly ( P=0.016) modified the association between CAR T-cell therapy and TLA among ALL patients. Specifically, transduced T cells exhibited a 0.46 higher ( P=0.053) and a 0.39 lower ( P=0.142) rate of TLA among patients 16 years of age or older and those younger than 16 years of age, respectively. Conclusions: We observed CAR T-cell therapy was associated with greater biological aging as estimated from DNA methylation among ALL patients and these associations are modified by chronological age. These findings suggest CAR T-cell therapy may be associated with age-related changes to the epigenome in ALL patients and strategies to limit or reverse this effect may have implications for the aging process in cancer survivors. [Table: see text]
Circulating metabolic profiling as a biomarker for immune checkpoint blockade efficacy.
Authors: Saldanha Erick Figueiredo , Lau Sally C. M. , Laister Robert C. , Wang Ben X , Penny Susanne , Pinto Devanand , Sacher Adrian G. , Saibil Samuel 
Published: June 2024

2564 Background: Immune checkpoint blockade (ICB) has changed the treatment landscape of non-small cell lung cancer (NSCLC). Despite being the mainstay of treatment for advanced NSCLC, the development of resistance to ICB is common. Hence, identifying biomarkers that can be used to select patients (pts) who will benefit from ICB is crucial. Here, we interrogate the circulating metabolome to identify the metabolic parameters associated with ICB effectiveness. Methods: This single-center retrospective analysis used a mass-spectrometry (MS) targeted metabolomics approach to assess the relative abundance of 115 metabolites in baseline (pre-ICB) plasma of 55 pts with advanced NSCLC. Pts treated with ICB at the Princess Margaret Cancer Centre from 2018-2020 were included. Electronic medical records were reviewed to collect clinicopathological and treatment data. All pts had tumour next-generation sequencing (NGS) by a targeted gene panel. Descriptive statistics were used to summarize the patient characteristics, treatment modalities, and outcomes. Time-to-event outcomes were analyzed using the Kaplan-Meier method. Progression-free survival (rwPFS) and overall survival (rwOS) were defined as the time from the first treatment dose to radiographic or clinical progression or death from any cause and time from the first dose of treatment to death from any cause, respectively. The response rate was assessed using RECIST 1.1. Statistical significance was determined as a p-value <0.05. Results: Amongst the 55 pts profiled, 42 (76.3%) had adenocarcinoma. The most common molecular alterations included KRAS (n=15), BRAF non-V600 (n=5), and METex14 (n=3). The median PD-L1 score was 65% (IQR 22.5 – 59%). All pts were treated with a single-agent PD-1 inhibitor, and 67.2% of pts received ICB as the first line of treatment. Metabolomic analysis of the pre-ICB initiation plasma samples identified 8 metabolites whose relative abundance significantly differed between responding (CR/PR) and non-responding pts (SD/PD). Amongst these metabolites was the endogenous danger signal Glucosylceramide (d 18:1/24:0), whose abundance was increased in the plasma of the responding pts. When we stratified pts by circulating levels of glucosylceramide, we found a statistically significant higher rwPFS (8.5 vs. 1.6 months, p=0.0001) and rwOS (13.5 vs. 6.1 months, p=0.0001) in pts who had high baseline plasma levels of Glucosylceramide (d 18:1/24:0) (top 50%) versus those with lower levels (bottom 50%). Conclusions: Utilizing a targeted metabolomics approach, we identified the metabolite and endogenous danger signal glucosylceramide (d 18:1/24:0) as a potential metabolic biomarker of response to ICB therapy. Future work will aim to validate this finding in a larger cohort and to understand the biological mechanism underpinning this correlation.
Proteogenomic profiling of clonal hematopoiesis in the solid tumor microenvironment.
Authors: Buttigieg Marco M , Vlasschaert Caitlyn , Rauh Michael J , Vanner Robert 
Published: June 2024

2567 Background: Clonal hematopoiesis (CH) is caused by somatic mutations that provide a fitness advantage in hematopoietic stem cells, contributing to inflammation and disease. CH is common in solid tumor patients, and has shown context-dependent associations with survival; however, its contribution to the tumor microenvironment (TME) remains unclear. Here, we employ proteogenomic methods to define CH-associated alterations in the TME. Methods: We tested 1,550 patients across 10 primary, treatment-naïve cancers in the Clinical Proteomic Tumor Analysis Consortium cohort. CH calls were derived from peripheral blood and tumour whole exome sequencing (WES) data, and CH was defined as the presence of a somatic driver mutation at variant allele frequency (VAF) ≥2% in blood. Overall survival (OS) analysis was conducted using Cox proportional hazard models, controlled for age, sex, tumor type, metastatic status, and smoking. Tumor bulk RNA-sequencing and mass spectrometry proteomics data were processed for differential expression and gene set enrichment analyses. Abundance of immune cell populations was estimated with CibersortX. Results: 349 CH mutations were identified in 283 patients (18.3%). CH was strongly associated with age and mutations were mostly found in the epigenetic regulators DNMT3A(37.8%, n=132) and TET2(20.6%, n=72). CH was most prevalent in ovarian cancer (30%, n=27/90) and colorectal cancer (CRC; 28.3%, n=30/106). 103 blood CH mutations were also detected in tumor WES (CHTum), with presence in the tumor associated with higher tumor immune infiltration and peripheral blood VAF ≥10%. CHTum, but not CH, was associated with worse OS (CHTum HR = 1.74 [1.13-2.69]; CH HR = 1.12 [0.83-1.50]). CHTum was also associated with a reduced likelihood of patients being classified as tumor free at follow up (OR = 0.39 [0.19-0.82]). We did not identify a pan-cancer proteogenomic signature of CH in the TME. At the tumor-specific level, we consistently observed associations between CH and its subtypes with dysregulated inflammation, with high transcriptomic-proteomic concordance. In CRC, TET2-mutant CH was associated with greater infiltration of CD4+ T cells, monocyte/macrophages, NK cells, and B cells, alongside an inflammatory response characterized by IL6/JAK/STAT3 signalling, TNF signalling via NFκB, and IL2/STAT5 signalling. Conclusions: CH is common, even prior to therapy, in solid tumor patients and the infiltration of CH-mutant immune clones into the TME is linked with poor outcomes. Beyond confounding molecular tumor diagnostics, CH in the TME also dysregulates the anti-tumor immune response, highlighting the value of a blood reference in precision oncology. The lack of a pan-cancer CH signature in the TME supports a tumor-specific influence of CH. Further study is needed for mechanistic discovery and biomarker development to realize the potential of CH in immuno-oncology and improve patient outcomes.