bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyaluronic acid hydrogel to modulate tumor cell clustering and programmed death ligand 1 signaling in cancer stem cells.
Authors: Basu Kaustuv , Mongeau Luc 
Published: June 2024

e14584 Background: The root of malignancy lies in the extracellular matrix (ECM) surrounding the stromal cells. Thus, current therapeutic targets manipulate abnormal tumor microenvironments (TME), which nourish cancer stem cells (CSC) and induce tumor cell clustering (TCC). Notably, despite the first line of clinical therapy with surgery and chemotherapy, uncontrolled self-renewal of CSCs, conversion of non-CSCs to CSCs, and TCC trigger cancer recurrence. The transmembrane glycoprotein CD44 is thought to be a potential master regulator in cancer recurrence as it interacts with hyaluronic acid (HA) in TME, expresses aberrantly on CSCs, induces TCC by homophilic interactions like Plakoglobin despite less understanding on their crosstalk, and promotes expression of pro-tumorigenic factor programmed death ligand 1 (PD-L1). Notably, CD44 is expressed in multiple isoforms, and splice isoform switching of CD44 dictates the properties of CSC, which still needs to be clarified. Hence, we aimed to characterize CSCs based on CD44 isoform expression, investigate the crosstalk between CD44 and Plakoglobin, and then design a novel injectable HA hydrogel that can disguise TME and suppress PD-L1 to combat cancer recurrence. Methods: To characterize CSCs, we prepared different scaffolds of HA of varied molecular weights and other ECM proteins, cultured cancer cells (MDA-MB-231, HeLa), and determined the expression of CD44 isoforms. We sorted CD44+/CD24- expressing CSC by flow cytometry. We implemented immunoprecipitation to detect the interaction between CD44 and Plakoglobin. We created a novel HA hydrogel composed of low and very high molecular weight HA, thiolated gelatin, and other components crosslinked with PEGDA. Using a torsional rheometer, we measured matrix stiffness. We assessed the cell proliferation efficiency of CSC by a colony-forming assay. Results: The study disclosed that CD44 isoforms expressed differently based on ECM properties. Matrix stiffness dictated CD44 isoform expression. We observed that CD44 interacted with Plakoglobin. CD44 ablation upregulated Plakoglobin significantly. Tumor suppressor p53 played a significant role in CD44-Plakoglobin crosstalk. We observed that the injectable hydrogel modulated CD44-Plakoglobin signaling and inhibited TCC, likely promoting anoikis. The hydrogel affected CD44 splicing and modified the activity of the CD44 intracellular domain, which interacts with PD-L1 and thus suppressed PD-L1 expression significantly in CSC. Conclusions: Currently, antibodies targeting PD-1/PD-L1 signaling have been clinically approved for various cancers. However, this regimen of treatment is expensive. We report a novel injectable hydrogel that can disguise TME, modulate CSCs and PD-L1, and may advance an alternative cost-effective avenue for cancer immunotherapy.
Expression of alternatively spliced PD-L1 RNA with skipping of transmembrane domain.
Authors: Charifa Ahmad , Lam Alfonso , Zhang Hong , Estella Jeffrey , Agersborg Sally , Mohtashamian Arash , Albitar Maher 
Published: June 2024

e14596 Background: Programmed death-ligand 1 (PD-L1) is a transmembrane ligand for the programmed cell death protein 1 (PD-1), a receptor that inhibits T-cell activity. The PD-L1/PD-1 immune checkpoint axis has been successfully targeted to enhance antitumor immune responses. This gene is composed of seven exons. Exons 1-4 are responsible for the extracellular domain, exon 5 for the transmembrane domain, and exons 6-7 for the intracellular domain. Emerging data indicates that alternative splicing in genes is an important mechanism for expression of different isoforms that may influence antibody-based therapies. We explored the potential of the presence of alternative splicing in PD-L1 transcripts via sequencing of PD-L1 RNA in patients with various type of solid tumor cancers. Methods: RNA was extracted from 3443 FFPE solid tumor samples including lung, colon, pancreas, breast, and other cancer types. In addition, cfRNA was extracted from 532 peripheral blood plasma samples from patients with solid tumor cancers. RNA was sequenced using a hybrid capture targeted RNA panel on FFPE samples and peripheral blood with analysis focused on PD-L1 gene transcript. Quantification of RNA transcript was done using Salmon algorithm. Results: Of the 3443 FFPE samples, 38 (1.2%) samples showed alternative splicing involving deletion of exon 5 (PD-L1∆Ex5). The alternative splicing was in 2.10% of lung cancer, 2% of colon cancer, 0.70% of pancreatic cancer, 1.40% of gastric cancer, 0.38% of breast cancer, 0.30% of ovarian cancer, 1.10% of sarcoma cases, 1.50% of glioblastomas, 3.30% of thyroid cancer and 2% of urothelial cancer. Of the 532 cfRNA samples, 20 (3.7%) showed PD-L1∆Ex5. The median percentage of PD-L1∆Ex5 transcripts was 2.2% of total PD-L1 transcripts in tissue samples as compared with 6.6% in cfDNA samples. In tissue samples, there was a correlation between levels of PD-L1 and PD-L1∆Ex5 (r = .567, p < .001). In contrast, cfRNA showed no significant correlation between levels of PD-L1 and levels of PD-L1∆Ex5 (r = .268). Conclusions: PD-L1 exon 5 skipping was detected in a number of patients with different types of solid tumor cancers. The percentage of skipping transcripts is low in cells and relatively higher in cfRNA. Since exon 5 skipping deletes the transmembrane domain, the PD-L1 protein may remain in the cytoplasm or perhaps is secreted as cell-free PD-L1 protein. The demonstration of relatively higher levels of PD-L1∆Ex5 in cfRNA is likely reflecting higher turnover of cells and raises the possibility that cells with this isoform of PD-L1 are more aggressive than cells without the expression of this isoform. Further studies are needed to explore the clinical relevance of the expression of such abnormal PD-L1 protein on treatment with immune checkpoint inhibitors.
Treatment-related adverse events of PD-1 versus PD-L1 inhibitors commonly used in lung cancer therapy: Analysis of real-world FAERS data.
Authors: Findakly Dawood , Beedupalli Kavitha 
Published: June 2024

e14598 Background: With the increasing utilization of immune checkpoint inhibitors (ICIs) in the dynamic landscape of cancer treatment, understanding immune-related adverse events (AEs) has become crucial for optimizing patient outcomes and therapeutic selection. In this study, we utilized the FDA Adverse Event Reporting System (FAERS) database to assess AEs reported with commonly used PD-1 and PD-L1 inhibitors in lung cancer therapy. Methods: We conducted a retrospective FAERS public database review to assess anti-PD-1 inhibitors (Pembrolizumab and Nivolumab) and anti-PD-L1 inhibitors (Atezolizumab and Durvalumab) reported AEs from January 2017 through September 30, 2023. We assessed disproportionality signals by calculating the reporting odds ratio (ROR) with a 95% confidence interval (CI). Significance was determined when the lower limit of the 95% CI exceeded 1. Results: In our analysis of 134,184 reported AEs, anti-PD-1 therapies had higher rates of cardiac AEs (ROR = 1.08; 95% CI: 1.03-1.14; P = 0.0015), vascular AEs (ROR = 1.23; 95% CI: 1.17-1.30; P < 0.0001), respiratory AEs (ROR = 1.30; 95% CI: 1.25-1.34; P < 0.0001), gastrointestinal AEs (ROR = 1.04; 95% CI: 1.01-1.08; P = 0.0117), hepatobiliary AEs (ROR = 1.12; 95% CI: 1.07-1.17; P < 0.0001), and renal and urinary AEs (ROR = 1.06; 95% CI: 1.01-1.11; P = 0.0195) compared to anti-PD-L1 therapies. Conversely, anti-PD-L1 therapies had higher rates of endocrine AEs (ROR = 1.31; 95% CI: 1.25-1.38; P < 0.0001), skin and subcutaneous tissue AEs (ROR = 1.43; 95% CI: 1.37-1.49; P < 0.0001), and musculoskeletal and connective tissue AEs (ROR = 1.33; 95% CI: 1.26-1.39; P < 0.0001) compared to anti-PD-1 therapies. Conclusions: Our study provides insights into the adverse event profiles of selected anti-PD-1 and anti-PD-L1 therapies in a real-world clinical setting. Further prospective studies are essential to enhance our understanding of the comparative safety profiles of these agents, guiding personalized treatment decisions and, ultimately, advancing patient outcomes.
Arthralgia in patients with cancer receiving immune checkpoint inhibitor: A systematic review and meta-analysis.
Authors: Nishimura Yoshito , Estaris Jonathan , Koseki Mako , Elias Evelyn , Chesta Fnu , Takaoka Kensuke , Shao Theresa , Fujiwara Yu 
Published: June 2024

e14601 Background: Immune checkpoint inhibitors (ICIs) have become an integral part of the standard therapeutic approaches for patients with cancer. However, the occurrence of immune-related adverse events (irAEs) occasionally poses challenges to quality of life (QoL). Despite the utility of ICIs in a daily practice, evidence about the frequency of arthralgia associated with ICIs, which severely affects QoL of patients with cancer, is limited. The study aimed to evaluate the incidence and treatment outcomes of arthralgia associated with ICIs. Methods: We performed a database search in PubMed/Medline, Embase, and Web of Science for phase 3 randomized control trials (RCTs) evaluating ICI therapy and reporting the incidence of arthralgia. The incidence of arthralgia was calculated in patients with solid tumors treated with ICIs. We performed a random-effect model meta-analysis to pooled odds ratios (ORs) of these outcomes using RCTs evaluating 1) the combination of ICIs with systemic therapy versus systemic therapy alone, 2) ICI vs chemotherapy (taxanes, non-taxanes, and mixed chemotherapeutic regimens) to assess the effect of ICIs on the incidence of arthralgia. I2 statistics was used to assess heterogeneity among the included studies and subgroups with I2 higher than 50% being considered high heterogeneity. Results: A systematic review identified 40 RCTs to analyze the incidence of arthralgia. The incidence of any-grade treatment-related arthralgia was 12.0% (n=1125/9395), and that of grade 3–5 treatment-related arthralgia was 0.54% (n = 47/8723). The addition of ICIs was associated with an increase in both any-grade (OR 1.32, 95% CI: 1.13–1.54, p = 0.001) and grade 3-5 arthralgia (OR 1.78, 95% CI: 1.08-2.94, p = 0.02: subgroup differences by ICB subtype: I2 = 0%). Subgroup analysis revealed that the addition of ICIs to cytotoxic chemotherapy was associated with an increase in the incidence of any-grade arthralgia (OR 1.35, 95% CI: 1.05–1.73, p = 0.02. The meta-analysis of ICI versus chemotherapy found that the incidence of arthralgia remained significantly increased when ICIs were compared with non-taxane chemotherapy (OR 6.83, 95% CI: 3.05–15.30, p < 0.00001), but not with taxanes (OR 0.74, 95% CI: 0.44–1.24, p = 0.25, I2 = 67%). Conclusions: Although the incidence of grade 3–5 arthralgia seems low, we revealed that the addition of ICIs to systemic therapy increased both any-grade and grade 3-5 arthralgia. Additionally, the incidence of any-grade arthralgia was more observed with ICIs than with non-taxane chemotherapy. In contrast, the incidence of arthralgia was not significantly different between ICIs and taxanes or mixed chemotherapy. The findings may be useful for patient education receiving ICIs for solid tumors. Future prospective studies are warranted to evaluate the therapeutic approach to grade 3–5 arthralgia and the need for ICI discontinuation.
Association between antibiotic use and mortality among older persons receiving first-line immune checkpoint inhibitors for non-small cell lung cancer (NSCLC).
Authors: Goldberg Chaya , Nelson Julia , Rua Melanie , Bannerji Rajat , Setoguchi Soko , Bates Benjamin 
Published: June 2024

e14607 Background: There is biologic plausibility that antibiotics (ABX) may reduce the effectiveness of cancer therapy, most notably immune checkpoint inhibitors (ICI). As ABX are commonly prescribed to older persons and more than a third of US persons with cancer are eligible for ICIs, use of ABX has important population health implications. We assess the association between ABX use and mortality among persons with NSCLC who receive first-line (1L) treatment. Methods: Using SEER-Medicare, we assembled a cohort of persons ≥66 years with NSCLC who received 1L treatment with platinum-based chemotherapy (PLT) or ICI (PLT without ICI, PLT with ICI, and ICI monotherapy) within one year of cancer diagnosis between 2017-2019. We assessed overall ABX exposure from 1 month to 1 year prior to treatment initiation and by ABX class. Primary outcome was all cause deaths within three years of treatment initiation or until 12/31/2020. Multivariable Cox proportional hazard models adjusting for individual-level characteristics (demographics, time-to-treatment, comorbidities, healthcare use, SEER registry, and neighborhood socioeconomic status) and landmark analyses of 1-6 months after cancer treatment were used to assess the association between ABX exposure and mortality. Results: Among 4,182 persons (mean age 75 years, 85% white, 68% chemo-immunotherapy within 2 months of NSCLC diagnosis), 63%, 18%, and 18% received PLT, PLT+ICI, and ICI, respectively. ICI+/-PLT increased in prevalence from 20% of treatments (2017) to 55% (2019). The mean age of persons who received ICI alone (78 years old) was higher than PLT or PLT+ICI. Prior to 1L treatment, 22% and 72% of persons received ABX within 30 days and 1 year prior to cancer treatment, respectively. The three most common ABX classes were fluoroquinolones (48%), penicillins (21%), and macrolides (18%). The cohort was followed for 3,274 person-years and included 2,958 deaths within 1 year and 4,144 deaths within 3 years of follow-up. Compared with persons who did not receive ABX within 3 months of cancer treatment, ABX use was associated with higher risk of death within 3 years for ICI alone [HR 1.24 (1.05-1.46) but not for PLT alone or PLT+ICI. Fluoroquinolones were associated with an elevated risk of mortality among persons who received ICI alone HR 1.41(95%CI: 1.1-1.8) and PLT alone HR 1.18 (95%CI: 1.05-1.32) but not PLT+ICI. Our findings were similar across definitions of ABX exposure (30 days to 1 year prior to treatment) and analytic landmarks after treatment initiation. Conclusions: Among patients with NSCLC who received 1L treatment, we identified an association between ABX exposure prior to treatment and increased mortality among persons who received ICI monotherapy but not PLT+ICI. As ICIs expand to more cancer types and earlier stages, ABX use may have a significant impact on outcomes and population health.
Effect of targeting DDR pathway on the late-phase autophagy and the killing effect of CD8+ T cells.
Authors: Li Guo , Xuan Chenghao , Zhong Diansheng , Zhang Linlin 
Published: June 2024

e14646 Background: Deficiency in DDR signaling pathways has been reported to be associated with better response to immunotherapy. This study aims to investigate whether inhibition of the key mediator of DDR pathways ATR could enhance the function of CD8+ T cells and its underlying mechanism. Methods: The CD8+ T cell-killing experiment was conducted in vitro to demonstrate the efficiency in the presence of ATR inhibitors. To investigate the regulatory mechanism, RNA Sequencing analysis was performed to identify gene changes after ATR inhibition. Subsequently, Western blotting and immunofluorescence assays were performed to access the autophagy flux based on the results of the RNA sequencing analysis. Flow cytometry was used to detect the surface MHC-I expression to validate our speculation with the change of autophagy activity. Results: ATR inhibitor (VX970) had been shown to enhance the cytotoxic effect of CD8+ T cells on tumor cells. RNA-seq analysis revealed the enrichment of pathways related to autophagy and its regulation, as well as inflammatory factor pathways. Accumulation of p62/SQSTM1 and an increased LC3II/I ratio had been found, indicating the involvement of autophagy after the inhibition of ATR. No further increase in autophagy proteins was observed upon treatment with autophagy inhibitors, suggesting the late stage of autophagy inhibition was affected. In addition, increased MHC-I molecular expression has been found in accordance with autophagy inhibition, which could further explain the reason ATR inhibition could induce the accumulation of CD8+ T cells. Conclusions: Targeting DDR pathway leads to stimulated CD8+ T cells accumulation probably by increased MHC-I surface expression through inhibition of late-phase autophagy, which may in turn enhance the efficiency of immunotherapy.
Preclinical studies of an innovative 5T4-ADC ACR246 with the potential to better treat 5T4-positive solid tumors.
Authors: Miao Zhenwei , Huang Yunsheng , Li Deliang , Wang Xiaobei , Sheng Guorong , Wang Feng , Wu Kai , Huang Xiuying , Yang Li , Li Yaowu , Weng Shanhui , Manchukonda Naresh kumar , LU Yao 
Published: June 2024

e15005 Background: 5T4 oncofetal antigen shows limited expression in normal adult tissues but highly expressed by many different cancers. It drives spread of cancer cells through epithelial mesenchymal transition (EMT), potentiation of CXCL12/CXCR4 chemotaxis and favoring non-canonical Wnt pathway, leading to poor prognosis of cancer patients. Besides, 5T4 has a highly efficient endocytosis ability which enables it to be an ideal target for the development of ADC drugs. A handful of 5T4-targeted ADCs have been evaluated in early phase clinical trials for several years showing only preliminary anti-tumor activity. However, uncertainty of their safety profiles has also raised concerns due to high toxic payloads, MMAF and duocarmycin, being used. Thus, additional approaches to this target with the potential of improved efficacy and reduced toxicity are needed urgently. ACR246, an innovative 5T4-targeted ADC consisting of specific humanized monoclonal antibody site-specifically conjugated with a cell penetrating and moderate toxic payload (DNA topoisomerase I inhibitor, D2102) that has a robust bystander effect through a stable and cleavable linker, with a drug-to-antibody ratio (DAR) of 8, was designed to improve the safety and efficacy in treating tumor patients. Methods: The pharmacologic profiles of ACR246 were assessed in vitro and in vivo including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, in 5T4-positive cell lines, cell-derived xenograft (CDX) models and cynomolgus monkeys. Results: ACR246 bound specifically to 5T4 and was internalized into tumor cells followed by D2102 release, which induced DNA damage, cell cycle arrest and apoptosis in 5T4 positive tumor cells in vitro. In vivo low systemic exposure and tumor-specific accumulation of D2102 rendered ACR246 superior efficacy and safety property. Accordingly, ACR246 exhibited robust in vivo anti-tumor activity across various types of 5T4 positive CDX models in a dose-dependent manner, with DNA damage induced by the accumulated D2102 in tumor tissue. GLP toxicity studies indicated that ACR246 was well tolerated in cynomolgus monkeys. The estimated therapeutic index was 24. Conclusions: The overall preclinical profile marks ACR246 has the potential to become the best in class (BIC) 5T4-ADC, showing more favorable benefit-risk ratio in clinic.
Hemay181: A novel SDC (sugar linked drug conjugate) for solid tumors targeting tumor microenvironment.
Authors: Jones Richard , Lv Jingjing , Fu Wei , Zeng Guanghuai , Zhang Hesheng 
Published: June 2024

e15006 Background: Hemay181 is a novel broad-spectrum conjugated cytotoxic drug for treating advanced solid tumours. The drug exerts its inhibitory effect on tumour growth by releasing cytotoxic drug SN-38 in tumour tissues via β-glucuronidase (βGU) metabolism to inhibit the activity of topoisomerase I (TOP1). The water solubility of Hemay181 is increased > 5000-fold compared to SN-38. Hemay181 also binds to plasma albumin to form a macromolecular drug transporter, significantly improving the drug's pharmacokinetics. In addition, βGU has low activity in normal tissues, localised to the lysosomes, but is highly expressed in the hypoxic tumour microenvironment. Methods: In vitro and In Vivo studies showed Hemay181 inhibited growth in 29 human tumour cell lines and 16 human tumor Xenograft models, including colorectal cancer, gastric cancer, triple-negative breast cancer, head and neck cancer, pancreatic cancer, lung cancer, prostate cancer and melanoma. Results: In the absence of βGU, Hemay181 showed significantly weaker inhibitory activity than Hemay181+βGU or no significant inhibitory activity. In these In vitro studies with the addition of βGU, the activity was similar to SN-38, ranging from 3.9 nM to 159 nM. Hemay181 showed tumor selectivity with low activity against two normal human cell lines. The IC50 values of Hemay181 against Chang liver (normal liver cells) and MRC 5 (embryonic lung cells) were 318 nM and 14566 nM under non-enzymatic digestion conditions. In vivo, Hemay181 had significant inhibitory effects on the growth of human colorectal cancer, pancreatic cancer, head and neck cancer, triple-negative breast cancer, lung cancer, liver cancer, ovarian cancer and gastric cancer tumour models. The lowest effective dose of Hemay181 was 1.875mg/kg in the human colon cancer HCT116 model. Within the dose range of 3.75~60 mg/kg, the highest inhibitory rate of the above different tumour models could reach more than 90%. Hemay181 significantly reduced tumour volume compared to irinotecan, which only slowed the tumour growth rates. There was no significant decrease in the body weight of Hemay181 in these studies. In the colon cancer PDX model (CR0029) (30mg/kg), the tumour inhibition rate (TGI) was 78%. At 60mg/kg, in triple-negative breast cancer (BR1458) and non-small cell lung cancer (LU3075) PDX models, a TGI was 97% and 98%, respectively. At 60mg/kg, there was a significant tumour suppressive effect on larger tumours treated with irinotecan, with a reduction of tumour volume. In vitro , 1 μM Hemay181 is stable in CD1 mouse and SD rat plasma, with a minor degree of metabolism in beagle dog, cynomolgus monkey and human plasma. Conclusions: In summary, the novel broad-spectrum anti-tumour drug Hemay181 has the characteristics of high water solubility, tumour-targeting ability, low toxicity and side effects on normal tissues. It is under evaluation in ongoing clinical studies.