bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic antitumor activity of METTL3 peptide degrader and immune checkpoint inhibitor in advanced urothelial cancer.
Authors: Shang Shihao , Han Hong , Liu Kepu , Li Zenghui , Zhang Jie , Zhang Lei , Ju Dongen , Wei Di , Yuan Jianlin , Zhu Zheng , Shi Junfeng
Published: June 2024

e14623

Background: In patients afflicted with advanced urothelial carcinoma (aUC), the durable response rate to immune checkpoint inhibitor (ICI) is approximately 20%. Recent study showed the pivotal role of N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) in immune escape and the progression of aUC. This study aimed to develop a novel METTL3 peptide degrader RKL and investigate its synergistic effects and underlying mechanisms in combination with ICI for aUC. Methods: Methyltransferase expression profiles were scrutinized using The Cancer Genome Atlas database; while the prognostic implications of METTL3 expression in response to ICI were analyzed in the IMvigor210 cohort study. Single-cell RNA sequencing (scRNA-seq) was employed to elucidate the mechanistic insights. The METTL3 peptide degrader RKL was synthesized using Fmoc solid-phase peptide synthesis and purified with high-performance liquid chromatography. In vivo and in vitro experiments were conducted to assess the impact of RKL, ICI, and their combination on aUC inhibition. Results: In aUC, METTL3 exhibited the most significant up-regulation among m6A methyltransferases, while METTL14 and WTAP showed down-regulated expression. In the IMvigor210 cohort study, aUC patients with elevated METTL3 expression and treated with ICI demonstrated a poorer prognosis. scRNA-seq revealed that METTL3 upregulation promoted the expression of genes regulating cancer-associated fibroblast proliferation, contributing to enhanced tumor resistance to immunotherapy. RKL demonstrated high toxicity to urothelial carcinoma cell lines, inhibiting their proliferative, migratory, and invasive capacities in vitro. The combined treatment of RKL and ICI significantly reduced tumor volume (P<0.001), with a complete response achieved in 87.5% (7/8) of mice in the combination group, 12.5% (1/8) in the RKL group, and 25.0% (2/8) in the ICI group. Conclusions: METTL3 overexpression in aUC is associated with immune escape and resistance to ICI therapy. The METTL3 peptide degrader RKL, when combined with ICI, demonstrates synergistic antitumor effects in aUC, warranting further exploration in clinical research.
Phase Ib study of a high potent PI3K-mTOR dual inhibitor WX390 combined with toripalimab in patients with advanced solid tumors.
Authors: Zhang Songling , Zhu Xiaoxue , Gao Lei , Qi Yaling , Jia Xiao , Li Yongguo , Guo Ye , Ding Yanhua
Published: June 2024

e14627

Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. It modulates the tumor immune microenvironment by decreasing tumor Treg and myeloid-derived suppressor cells (MDSC) and improves the immune response to checkpoint inhibitors (CPI) in preclinical models. Methods: The Phase Ib study was designed to evaluate safety, pharmacokinetics (PK), and preliminary clinical activity, to determine recommended phase 2 dose (RP2D) of WX390 combined with Toripalimab in patients with advanced solid tumors. WX390 was administered orally daily at escalating doses of 0.7 mg, 0.9mg and 1.1mg, with Toripalimab at 240 mg IV every 3 weeks until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma PK samples were collected up to 24 hours after the first dose at C1D1, and up to 24 hours before and after the morning dose at C1D21. Results: As of December 31, 2023, total 18 patients had been treated in 3 WX390 cohorts: 0.7 mg (n = 3), 0.9 mg (n = 3), and 1.1 mg (n = 12) once daily (QD). No dose limit toxicity (DLT) was observed, and the RP2D of WX390 in combination was 1.1 mg QD, which was consistent with the single agent RP2D. The treatment related adverse events (TRAEs) (≥20%) included hyperglycemia (17/18, 94.4%), creatinine increased (12/18, 66.7%), weight loss (10/18, 55.6%), diarrhea (9/18, 50%), proteinuria (9/18, 50%), nausea (7/18, 38.9%), lymphocytopenia (7/18, 38.9%), vomiting (7/18, 38.9%), rash (7/18, 38.9%), decreased appetite (6/18, 33.3%), hypokalemia (6/18, 33%), fatigue (5/18, 27.8%), hyponatremia (4/18, 22.2%), and thrombocytopenia (4/18, 22.2%). Grade 3 TRAEs included hyperglycemia (5/18), lymphocytopenia (4/18), rash (2/18), weight loss (2/18), leukopenia (1/18), infusion-related reaction (1/18), nausea (1/18), and stomatitis (1/18). There was no TRAE leading to treatment permanent discontinuation and no grade 4/5 TRAE were observed. PK of WX390 in combination showed similar PK profile with the single agent. Among the 16 efficacy-evaluable patients with cervical (N=8), head and neck (N=5), and urothelial cancer (N=3), 5 patients (31.3%) previously received immune checkpoint inhibitors. 3 of 5 (60%) cervical cancer patients at RP2D and 2 of 5 head and neck cancer patient (40%) have achieved confirmed partial response (PR). In addition, 3 cervical patients who were treated with 0.7 or 0.9mg QD and 1of 3 urothelial carcer patients experienced tumor shrinkage (SD). The medium progression free survival (PFS) was 5.49 months (95% CI: 2.53, 6.37). Conclusions: WX390 in combination with Toripalimab had a manageable safety profile and encouraging antitumor effects in patients with advanced solid tumors. An RP2D of 1.1 mg qd of WX390 in combination was selected to be explored in further phase II study, which is ongoing in different tumor types. Clinical trial information: NCT06117566 .
Tumor-derived ILT3 inhibition to reshape the immunosuppressive microenvironment and potentiate the PD-L1 blockade immunotherapy in lung adenocarcinoma.
Authors: Wang Leirong , Sun Yanxin , Li Juan , Gao Aiqin , Wang Shuyun , Fu Xuebing , Wang Xiufen , Sun Yuping
Published: June 2024

e14647

Background: The low response of immune checkpoint inhibitors against PD-1/PD-L1 in cancer patients calls for further development of new immune targets. Immunoglobulin-like transcript (ILT)3 and its ligand ApoE have been demonstrated to be highly expressed in a variety of malignant tumor cells and involved in tumor biological behaviors, including invasion and angiogenesis. ILT3 targeting drugs are undergoing increasing preclinical and clinical trials. However, the role of tumor-derived ILT3 in immune regulation is unclear. The aim of this study was to investigate the immunomodulatory effect of tumor-derived ILT3 and its immunotherapy therapeutic efficacy that combination with PD-L1 blockade in NSCLC. Methods: The correlations between ILT3/ApoE expression and prognosis of NSCLC patients were analyzed basing on public databases. Multiplex immunofluorescence was performed to analyze the correlations between tumor-derived ILT3/ApoE expression and intratumoral immune cells infiltration in human adenocarcinoma tissues. The impact of ILT3 and ApoE on tumor-associated macrophage (TAM) recruitment and polarization were evaluated by transwell migration assay, flow cytometry, and RT-PCR, while their direct impact on T cell survival and cytotoxicity was detected by flow cytometry. Using lung cancer xenograft murine models, we further confirmed the pro-tumoural activity of tumor-derived gp49B and analyzed its correlations with immune cells in vivo. Tumor immunotherapy models targeting at gp49B and/or PD-L1 were established in C57BL/6 mice inoculated with LLC cells. Gp49b inhibition was implemented by infection of specific knockdown lentivirus and PD-L1 was blocked using mouse neutralizing antibodies. Flow cytometry was performed to detect the frequency and phenotype of macrophages and T cells in the tumors, spleen, and blood of the mice. Results: Patients with high expression of ILT3 had significantly worse prognosis in LUAD, but not in LUSC. In vitro assays demonstrated that tumor-derived ILT3/ApoE promoted recruitment and M2-like polarization of TAMs and directly inhibited the proliferation and cytotoxicity of T cells, which had been further confirmed in vivo models. Moreover, ILT3 (gp49B) inhibition enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell- induced immunosuppressive TME; the combined inhibition of gp49B and PD-L1 showed the most dramatic tumor retraction in LLC xenograft models. Conclusions: Tumor-derived ILT3 overexpression suppressed anti-tumor immunity by recruiting M2-like TAMs and directly impairing T cell activities, while ILT3 inhibition counteracted above immunosuppression and potentiated the efficacy of PD-L1 blockade in LUAD. Our study verified that ILT3 may be a promising novel immunotherapeutic target for LUAD patients.
Tumor purity as confounder for the determination of tumor mutational burden (TMB).
Authors: Beck Susanne , Menzel Michael , Kazdal Daniel , Schirmacher Peter , Stenzinger Albrecht , Budczies Jan
Published: June 2024

e14656

Background: TMB determination is a prerequisite to stratify advanced cancer patients for pembrolizumab based on the histology-agnostic FDA approval. The accuracy of TMB measurement is challenged by low tumor purity resulting in a lower number of detected somatic variants for a fixed threshold of variant allele frequency (VAF) and a lower measured TMB level as a consequence. Methods: We derived a mathematical formula describing the influence of tumor purity on the VAF of somatic variants, in which the DNA copy number of the corresponding region of the tumor genome is a parameter. We simulated the effect of tumor purity in a cohort of 4,900 tumors from the TCGA project with tumor purity of at least 80%. TMB was calculated as the number of missense mutations with VAF greater or equal than 5%. Tumors were classified as TMB-high when harboring at least 199 missense mutations. This cutpoint corresponds to 10 mut/Mb as derived in the TMB bridging study. We compared tumors with a simulated tumor purity of 70%, 60%, ..., and 10% with tumors with a tumor purity of 80%, which served as reference. Results: The median of TMB in the pan-cancer cohort was reduced by 2%, 10%, and 32% for tumor purity of 60%, 40%, and 20% compared to the reference of 80%. For the 10% tumors with the worst estimation, TMB was reduced even by 12%, 35%, and 77% or more, respectively. In the pan-cancer cohort, the sensitivity to detect high TMB was 98%, 90%, and 62% for tumor purity of 60%, 40%, and 20%, respectively. For head and neck cancer, lung adenocarcinoma, lung squamous cell carcinoma, and cutaneous melanoma, the sensitivity to detect high TMB was 80%, 89%, 92%, and 91%, respectively, for tumors of tumor purity 40%. Conclusions: High tumor purity is critical for accurate determination of the TMB and to reach a high sensitivity concerning the selection of patients for immunotherapy. As shown by the simulations, the sensitivity to detect high TMB is close to 100% for tumor purity of at least 60%, while a substantial proportion of patients that could receive immunotherapy is missed for tumors with purity of 40% or less. Potential ways out of the TMB underestimation include increasing the sequencing coverage and lowering the VAF threshold for mutation calling or using clonal TMB with an adapted cutpoint instead of total TMB as biomarker for immunotherapy guidance.
TERT-associated DNA polymerases genes link CAF and CD8+ T Cells to improve immunotherapy response rate across multiple cancers.
Authors: Luo Zhiwen , Che Xu , Xie Yaoyu , Deng Yiqiao , Che Yun , Bi Xingang , Zhao Hong , Bi Xinyu
Published: June 2024

e14669

Background: The cancer cells exhibit heightened basal levels of responses to DNA breaks, accumulating DNA polymerases family (DNA-pol) as repair protein, thereby increasing DNA mutation and neoantigens. Based on this, we investigated the potential of DNA-pol as an immunotherapy biomarker and its underlying mechanism. Methods: We conducted a pan-cancer analysis of DNA-pol gene dysregulation in 6366 samples. Normal fibroblast, cancer-associated fibroblast, and CD8+ T cells were cultured from cancer patients (3 esophagus, 5 lung, 5 renal, and 3 liver cancer), then treated them with PD-L1 inhibitor or overexpressing TERT for RNA-seq and proteomics. 996 multiple cancer cases with ICIs were collected to test biomarker efficiency. A phase II clinical trial is evaluating and exploring our biomarker in mechanism prospectively. Results: We defined a distinct signature score of DNA-pol genes upregulated in cancer (DNA-pol-up) and linked to worse prognosis (HR=1.2). DNA-pol-up program dysregulation led to immune processes alteration and was related to upstream activation of TERT signaling (z-score=3.6) in ingenuity pathway analysis and linked to immunologically active tumors by recruiting CD8+ T cell and downregulating CAF. DNA-pol-up score was elevated in PD-L1-treated CAF and TERT-overexpressed CD8+ T cell, in MSI-H cancer, also related to more neoepitope peptides, TMB (Rho=0.54), cancer stemness (Rho=0.78), and tumor purity (Rho=0.29). Cancers that activate this program carried distinct genomic profiles with PIK3CA, KRAS, and TP53 mutations. This signature was an independent predictor for ICIs response (OR=2.52), even outperforming cytolytic activity, MSI, TMB (OR=0.9). In 12 clinical trial datasets, this signature could stratify the responding patients (maxAUC=0.762). In our phase II clinical trial, 34 liver cancer were enrolled with 4-year follow-up, it also has a satisfactory performance in predicting the ORR (AUC=0.699) and classifies mortality rate (HR=2.5), meanwhile verified its relationship with detailed potential molecular mechanism. Conclusions: Our findings identify a distinct transcriptional pattern of DNA-pol genes across cancers, which highlighted the role of DNA-pol family genes in predicting the immunotherapy response for the first time, and TERT could be a novel vaccine candidate for improving immunotherapy response.
ITHindex: An integrated tool for quantifying intra-tumor heterogeneity using omics data in cancers.
Authors: Liu Yutao , Jiang Yuan , Xie Wenchuan , Zhao Jing , Wang Guoqiang , Cai Shangli , Wen Yongqin
Published: June 2024

e14689

Background: Intra-tumor heterogeneity (ITH) is a hallmark of cancer and plays a significant role in tumor evolution, treatment response, and the development of drug resistance. However, there is currently no standardized metric for assessing ITH in clinical practice. Several recent studies have proposed different algorithms of ITH based on multi-omics data. In this study, we have developed a web-based tool for analyzing tumor heterogeneity using diverse omics data and investigated the correlation between different ITH algorithms using TCGA data. Methods: We collected previously published ITH algorithms based on single-/multi-region genomic, transcriptomic, and proteomic data. We integrated these algorithms into a web server called ITHindex, which utilizes Shiny framework. TCGA data was employed for a comprehensive comparison of five ITH algorithms including MATH, CNH, DEPTH2, Shannon index and DITHER. Results: ITHindex (https://xwen.shinyapps.io/ithindex/) is an open-access online tool that encompasses a total of eight algorithms. Based on the type of input data, these algorithms can be categorized into SNV, cancer cell fraction (CCF), copy number variations segment, bulk or single-cell RNAseq, and multi-region mass spectrometry of protein. According to the calculation principles, these algorithms include those based on Shannon entropy, MAD, tumor clonality, ratio, and distance. To demonstrate the practicality of ITHindex, we employed TCGA data to calculate ITH values using five algorithms. The analysis unveiled that the distribution of the same algorithm differs across various tumor types. When considering the same type of input data, different algorithms exhibited a strong correlation. Furthermore, with the exception of MATH, the other ITH values displayed a negative correlation with overall survival. Conclusions: ITHindex is a user-friendly web-based tool that quantifies intra-tumor heterogeneity, empowering researchers to investigate the role of ITH in oncologic biology.
Reporting of immune-related adverse events (irAEs) in US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.
Authors: Tapiavala Shaili , Shenouda Mina A. , Patel Vaibhav G. , Davis Andrew A.
Published: June 2024

e14693

Background: Evaluating immune checkpoint inhibitor (ICI) toxicity is complex given the interplay between the host immune system and tumor microenvironment leading to unpredictable timing and severity of irAEs. Monitoring of irAEs is critical as they can cause significant impact on morbidity and quality of life. Thus, we evaluated the consistency and pattern of reporting of irAEs in trials leading to FDA drug approvals. Methods: Using the FDA website, we identified 73 primary articles for ICI FDA approvals over a 10-year period (2011-2021). Data were collected independently by all authors as categorical variables for reporting of any grade and grade 3 or higher toxicity in the trial arm that led to FDA approval for 29 irAEs classified by the National Comprehensive Cancer Network Version 1.2024 guidelines. Our analyses were based on a binary classification of reported versus not reported, including the manuscript text, tables, and supplement, and reporting trends were analyzed based on the study year, phase, primary tumor, and monotherapy versus combination ICI therapy. Results: The majority of approvals were associated with Phase II (N=22) or Phase III (N=39) studies. Approvals included 14 primary tumors and 2 tumor agnostic approvals with the most common tumors including lung (N=22) and skin (N=14). irAE reporting ranged between 0% and 100% with a mean of 40% and a standard deviation of 35. Across the 29 irAEs, 45% were categorized as severely underreported with less than 25% reporting in trials, 17% were classified as underreported in 26-50% of trials, 17% were moderately reported in 51-75% of trials, and 21% were well reported in at least 75% of trials. For example, fatigue, diarrhea, and hypothyroidism were well reported at 100%, 99%, and 93%, respectively, while myocarditis, aseptic meningitis, and giant cell arteritis were severely underreported at 18%, 4%, and 1%, respectively. Additionally, certain systems were more reported than others, including gastrointestinal (100%) and endocrine (97%), while other systems were inconsistently reported such as cardiology (15%) and neurology (48%) (see Table). Conclusions: Our study identified significant inconsistencies in irAE reporting in clinical trials that led to ICI FDA approvals. In particular, rarer irAEs were reported infrequently while more common irAEs were well reported. Unified efforts are needed to standardize the irAE reporting in the primary literature to ensure reliable dissemination of information for timely recognition and treatment in clinical practice. [Table: see text]
Routine documentation of pre-treatment functional variables to predict survival in patients on immunotherapy.
Authors: Faucheux Andrew Thomas , Olson Eric , Hunting John , Klepin Heidi D. , Elko Catherine A. , Deyo Logan James , Lycan Thomas William
Published: June 2024

e14701

Background: Medical providers often describe concerns about a patient’s functional status in routine clinical documentation (e.g., hard of hearing, recent falls, difficulty with home medication). These clinician-documented pretreatment functional variables (PFVs) may be predictive of outcomes among patients receiving immunotherapy. The goal of this retrospective study is to check for an association between the documentation of PFVs with overall survival (OS), progression-free survival (PFS), and the incidence of immune-related adverse events (irAEs). Methods: We created a retrospective registry of all patients who received at least one dose of an immune checkpoint inhibitor for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center. The investigators created a validated REDCap registry; clinical research specialist at Vasta Global captured most data. PFVs were collected by review of routine clinical documentation 30 days before or after the first dose. Patients were stratified by their number of PFVs (0,1, or 2+) and by their age (≥ or <65 years). PFVs assessed function, nutritional status and social support and were dichotomized to indicate impaired vs not with ten total categories. We used Cox proportional hazard modeling for survival analyses between the three PFV groups, calculated from the first dose of immunotherapy to disease progression, death, and last known follow-up controlling for age, BMI, smoking, and disease type with a two-sided alpha of 0.05. Results: From the overall cohort (n = 3,101), 35% had no PFVs, 32% had one PFV, and 32% had two or more PFVs; 52.5% were considered younger, and 47.5% geriatric-aged (≥65yo). PFVs were more common among the geriatric-aged population (mean 1.43 vs 0.89). The most common cancer types were lung cancer (45%), melanoma (14%), and kidney (6%). The most noted PFVs were visual impairment (26%), unintentional weight loss (22%), inability to walk a quarter block (17%), living alone (16%), and falls (14%). In the overall population, an increasing number of PFVs was associated with shorter OS. When stratified by age, the number of PFVs was associated with shorter progression-free survival (p <0.01) and overall survival (p <0.01) among the geriatric and non-geriatric populations (Table). There was no association between increasing PFVs and incidence of irAEs. Conclusions: Although often considered to be signs of aging, documentation of multiple PFVs was associated with worse OS and PFS among geriatric-aged and non-geriatric-aged populations. This study highlights the utility of routine clinical documentation on health status, including function, nutrition, and social support, to estimate survival regardless of chronologic age. [Table: see text]
Pre- and post-radical surgery comparative quantification of circulating tumor cells and circulating tumor-associated cells.
Authors: Datar Rajan , Datta Vineet , Akolkar Dadasaheb , Chougule Rohit , Patel Shoeb , Shejwalkar Pradyumna , Adhav Archana , Dalvi Apurva , Patil Darshana
Published: June 2024

e15056

Background: Classical Circulating Tumor Cells (CTCs) are defined as EPCAM+, PanCK+, CD45-, whereas, Circulating Tumor Associated Cells (CTACs) are defined as EPCAM+, PanCK+, CD45+/-. CTACs comprise a heterogenous mix of tumor-associated cells including classical CTCs, cancer stem cells, circulating micro-emboli, tumor cell fused macrophages and other tumor-educated cells including junction endothelial and stromal cells. These cells play either a causative or synergistic role in the metastatic spread of cancer. Although it has been speculated that CTCs and CTACs would be rapidly cleared once tumor burden diminishes, the effect of radical surgery in cases of solid organ cancers and the change in the quantum of these cells after surgery has not been fully explored. Methods: We obtained 15 ml peripheral blood from 20 patients diagnosed with solid organ cancers comprising head and neck (11/20, 55%), breast (4/20, 20%), and colorectal (5/20, 25%) before and immediately after (within 24 hrs.) radical surgery. Peripheral Blood Mononucleated Cells (PBMCs) were isolated after RBC lysis and CTCs and CTACs were identified and enumerated from the same sample using differential apoptosis based negative enrichment followed by fluorescent imaging. Results: Pre-surgery, CTCs ranged from 12 to 0 cells per ml and 0 to 2 per ml post-surgery. CTACs ranged from 17 to 11057 cells per ml and, post-surgery, from 4 to 2041 cells per ml of blood. After surgery, CTCs were eliminated in 19/20 (95%) specimens, and in 1/20 (5%) specimens, there was a slight increase in the number of CTCs post-surgery. In 16/20 (80%) patients, the CTACs reduced by > 80%; in 2/20 (10%) patients, the CTACs reduced by > 50%-<80% and, in 2/20 (10%) patients, CTACs increased by > 5%. Conclusions: The enumeration of CTCs appears to correlate with the tumor burden pre- and post-surgery. On the other hand, although there appears to be a significant reduction in CTACs, residual cells of this phenotype appear to persist. The clinical correlation of this divergent trajectory of CTCs and CTACs pre- and post-surgery warrants further long-term studies.
Dual analysis of IL-8 in non-small cell lung cancer: A clinical perspective on protein and RNA evaluation via imaging mass cytometry.
Authors: Ramos Corinne , Gerstenberg Amandine , Boute Melodie , Lapage Marie
Published: June 2024

e15068

Background: The cytokine Interleukin-8 (IL-8) plays a pivotal role in the tumorigenesis and progression of non-small cell lung cancer (NSCLC), influencing both the tumor microenvironment and immune escape mechanisms. Given its significance, accurately assessing IL-8 levels at the protein and RNA levels could provide valuable insights into its prognostic value and inform therapeutic targeting strategies. This study utilizes imaging mass cytometry (IMC) to conduct a comprehensive evaluation of IL-8 expression in NSCLC, integrating both protein presence and gene expression analysis within the spatial context of the tumor microenvironment. Methods: Our approach leverages the capabilities of IMC to simultaneously detect protein and RNA levels of IL-8 in NSCLC tissue samples. For protein analysis, antibodies tagged with heavy metal isotopes specifically target IL-8, allowing for precise quantification and spatial localization within the tumor. Concurrently, RNA detection is achieved through hybridization probes designed for IL-8 mRNA, enabling the direct observation of gene expression patterns. This method provides a unique opportunity to correlate IL-8's protein abundance with its mRNA expression, offering insights into the regulatory mechanisms at play and their impact on the tumor's behavior and patient outcomes. Results: Preliminary data demonstrate a marked heterogeneity in IL-8 distribution at both the protein and RNA levels, with distinct patterns emerging that relate to tumor aggressiveness and immune infiltration. High IL-8 expression, identified through our integrated IMC approach, correlates with poor prognosis and reduced response to standard therapies, underscoring its potential as a biomarker for NSCLC management. Furthermore, the spatial analysis afforded by IMC highlights the microenvironmental niches where IL-8-mediated interactions could drive tumor progression and immune evasion. Conclusions: By employing IMC for the dual analysis of IL-8 protein and RNA in NSCLC, our study provides a comprehensive view of this cytokine's role in lung cancer pathology. The ability to visualize and quantify IL-8 expression within the spatial context of the tumor microenvironment opens new avenues for understanding its biological impact and for developing targeted therapies. Our findings advocate for the inclusion of IL-8 in the biomarker panel for NSCLC, with potential implications for patient stratification and personalized treatment planning. Future research will focus on expanding these observations to a larger cohort and exploring the therapeutic modulation of IL-8 as a strategy for improving NSCLC outcomes.
Initial clinical experience with the first-in-class anti-metastasis therapeutic TTX-MC138.
Authors: Medarova Zdravka , Robertson Neil , Ghosh Subrata , Duggan Susan , Varkaris Andreas
Published: June 2024

e15072

Background: TransCode is focused on developing nucleic acid-based cancer therapies. Through scientific discovery efforts, miRNA-10b was identified as a master regulator of the viability of metastatic tumor cells. This knowledge allowed development of a therapeutic strategy based on miR-10b inhibition. miR-10b was targeted using antagomirs delivered to metastatic sites by an iron oxide nanocarrier, termed TTX-MC138. Results demonstrated that TTX-MC138 could cause complete and persistent regressions of metastases in cancer models. Methods: TransCode has an active eIND and is conducting a Phase 0 clinical study with radiolabeled TTX-MC138 in patients with advanced metastatic cancer of multiple tissue origins. TTX-MC138 was radiolabeled with Cu64 through a NODAGA chelator. IND enabling studies were conducted in rats and non-human primates to support FDA activation (eIND163800) for the Phase 0 clinical study. In the trial, a single intravenous microdose of Cu-64 labeled TTX-MC138 is administered, which allows for direct visualization of drug tissue distribution in cancer patients via PET-MR imaging. Results: Non-clinical studies were conducted to support the TTX-MC138 clinical development program. In rats, when TTX-MC138 was infused intravenously at a dose of 27 mg/kg, results displayed a blood half-life of 16.7±9.35 hrs. At 24-h, concentrations were highest in the liver and spleen. In non-human primates injected with Cu64-labeled TTX-MC138 at a dose of 100 microg, the organs with the highest uptake were the liver, heart, lung and spleen. The mean whole blood half-life was 12.2 ± 2.3 h (mean ± standard deviation). RadioHPLC analysis of plasma samples showed that the drug is very stable with respect to metabolism. A study in rats involved a single injection with 0, 0.5 or 1 mg/kg followed by a 2-day or 14-day observational period. The drug was well-tolerated at levels up to 1 mg/kg, which was considered to be the no-observed-adverse-effect-level (NOAEL). Preliminary results from the Phase 0 clinical study showed that the first patient tolerated the dosing with no reported adverse reactions, the drug remained stable in circulation, and circulated with a long half-life of 20 hours. Lesion to blood ratios of radioactivity in the region of the metastatic lesions was consistent with accumulation of TTX-MC138. Enrollment, data monitoring, and analysis is ongoing. Conclusions: The results of the non-clinical studies and Phase 0 clinical study have the potential to address the question of delivery to the target tissue. The process leading to the implementation of TTX-MC138 in the clinic is critically dependent on the innate tropism of the TTX delivery platform to tumors and represents a first step towards developing effective nucleic-acid based therapeutics against cancer. Clinical trial information: NCT05908773 .
A phase II study of liposomal irinotecan-based chemotherapy with or without PD-1 inhibitor in patients with unresectable locally advanced or metastatic biliary tract cancer.
Authors: Ying Jieer , Cheng Xiangdong , Xu Qi , Li Jingjing , Zhuo Yiwen , Liu Yanping , Yuan Jing
Published: June 2024

e15077

Background: Clinical outcomes for advanced biliary tract cancer (BTC) patients (pt) progressed on first-line therapy remain dismal. Liposomal irinotecan (LI) (HE072) is a formulation encapsulating I in a lipid bilayer vesicle and was approved in China in September 2022. It was used with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic pancreatic cancer progressing on gemcitabine treatment. We conducted an phase II study to investigate HE072 in combination with 5-FU and LV with or without a novel PD-1 inhibitor SG001 in patients with advanced BTC progressed on prior gemcitabine-based chemotherapy. Methods: This is a multi-center, non-randomized, open label phase II study in pts with unresectable locally advanced or metastatic BTC. Key inclusion factors were ECOG PS 0-1, prior gemcitabine-based chemotherapy, evidence of disease progression with at least one measurable lesion and adequate haematological/organ function. Key exclusion factor was brain metastases. Pts were treated with liposomal irinotecan (70 mg/m2) plus LV (400 mg/m2f) and 5-FU (2400 mg/m2) with or without SG001 (240mg) IV every 2 weeks for up to 2 years in absence of disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Primary endpoint was objective response rate (ORR). Secondary endpoints include progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: As of April 25, 2023, 17 BTC pts were enrolled into liposomal irinotecan-based chemotherapy arm (n = 7) and liposomal irinotecan-based chemotherapy plus SG001 arm (n = 10). ORR and DCR were 14.3% and 71.4% for chemotherapy arm, 20% and 40% for chemotherapy+ SG001 arm. Median OS and PFS for chemotherapy arm was 11.5(95% CI, 3.9-NE) and 4.2(95% CI, 1.4-NE) months, and for chemotherapy+PD-1 arm was 15.3 (95% CI, 3.6-17.0) and 3.8(95% CI, 1.4-6.9) months. All pts experienced treatment-related adverse events (TRAEs). The incidence of grade≥3 TRAEs was 58.8%(10/17), which occurred in 57% (4/7) of pts treated in chemotherapy arm vs 60% (6/10) in chemotherapy+SG001 arm. Among all patients, the most frequent grade ≥3 TRAEs were fatigue (29.4%), neutropenia (23.5%) and leukopenia (23.5%). One grade 4 TRAE leading to dose reduction in liposomal irinotecan was febrile neutropenia in chemotherapy arm. There were no treatment-related deaths. Conclusions: These preliminary results suggested that liposomal irinotecan plus 5-FU and LV was well-tolerated and showed promising and durable clinical activity in advanced BTC pts progressed on first-line treatment. Combined use of SG001 further improved clinical outcome in these pts without increased toxicity. Combination of liposomal irinotecan, 5-FU, LV and PD-1 inhibitor is a treatment strategy which is worthy of further exploration.
Performance of surufatinib in treating advanced neuroendocrine neoplasms: Insights from a real-world study.
Authors: Zhu Linhui , Ye Xuan , She Youjun , Liu Wensheng , Du Qiong , Zhai Qing
Published: June 2024

e15124

Background: Current comparisons of targeted treatments for advanced neuroendocrine neoplasms (NENs)-specifically surufatinib, sunitinib, and everolimus—are lacking. This study aims to assess their efficacy and safety in a real-world setting. Methods: A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs prescribed surufatinib, sunitinib or everolimus between July 2020 and April 2023. The primary outcome was median progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR) and adverse events (AE). Results: A total of 123, 56 and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib or everolimus were enrolled. In pancreatic NENs (pNEN), surufatinib demonstrated superior efficacy over sunitinib and everolimus combined (mPFS: 8.67 vs 6.37 months, P=0.02; ORR: 17.1% vs 8.3%). Specifically, surufatinib outperformed sunitinib (mPFS: 8.67 vs 6.40 months, P=0.04; ORR: 17.1% vs 10.9%) and everolimus (mPFS: 8.67 vs 5.37 months, P=0.05; ORR: 17.1% vs 3.8%) individually. In extrapancreatic NENs (epNEN), surufatinib showed enhanced efficacy compared to everolimus (mPFS: 9.47 vs 6.70 months, P=0.15; ORR: 8.3% vs 5.3%). On multivariate Cox analysis, male, functional status, Ki67 index>20%, previous SSA and germline mutation, poor differentiation, liver metastasis, multi treatment lines were identified as negative effect (P<0.05) for PFS in pNEN and epNEN patients respectively. The most common adverse events (AEs) were hypertension (12.2%) in surufatinib-treated patients, manageable with medication. Sunitinib led to decreased neutrophil counts (10.7%), and everolimus was associated with anemia (4.4%). Conclusions: Utilizing real-world data, this study reveals surufatinib significantly enhances progression-free survival (PFS) over sunitinib and everolimus in advanced neuroendocrine neoplasms (NENs), guiding future targeted treatment choices.
Clinical efficacy of a next-generation sequencing (NGS) and immunohistochemistry (IHC) panel in patients with advanced cancer in Argentina.
Authors: Cantarella Florencia , Mendoza Bertelli Andrea , Girotti Romina , Marino AnaClara , Brest Esteban , Dibarbora Delfina , Mahmoud Yamil , Veigas Florencia , Enrico Diego Hernán , Tsou Florencia , Lacava Juan A. , Piazzoni Luciano , Riso Aldo Alejandro , Martinengo Gastón L. , Rodriguez Andres , Beguelin Zenon , Cerrato Sebastian , Jerez Ignacio , Salanova Ruben
Published: June 2024

e15154

Background: The analysis of somatic genomic alterations, evaluation of DNA mismatch repair (MMR) proteins, and examination of PD-L1 expression in tumor biopsies are crucial for prognosis and informed therapeutic decisions. However, their clinical implementation in Argentina faces challenges due to economic costs and lack of evidence. To address this, we conducted a retrospective study to assess the impact of this molecular panel testing on treatment decisions and clinical management of cancer patients in Argentina. Additionally, we evaluated its ability to detect clinically relevant alterations and analyzed the frequency and co-occurrence of mutations in our cohort. Methods: Tumor tissue samples from 266 patients with primary tumors, representing 26 different anatomical sites (53% lung cancer), underwent molecular testing using the Optimus panel developed by Biomakers. The assay integrates somatic sequencing of 52 genes through NGS with IHC assessment of MMR and PD-L1 proteins. A retrospective evaluation of the clinical effectiveness of the test was conducted on 133 patients. Genomic and clinical data were analyzed using R with the pairwise Fisher’s exact test applied for statistical analysis. Results: This panel facilitates molecular characterization, identifying clinically relevant genetic alterations in 65% of patients and detecting deficiency in MMR proteins in 3%. Findings align with global clinical trial availability for identified alterations in 97% of cases. KRAS is the most frequently mutated gene (38%), followed by EGFR (19%), PIK3CA (12%), BRAF (9%), CDK4, and CTNNB1 (5% each), correlating with lung cancer overrepresentation. Simultaneous alterations in EGFR, PIK3CA, CTNNB1, and KIT genes were observed. Pan-tumoral interaction analysis revealed mutual exclusivity between KRAS mutations and those in EGFR, BRAF, CDK4, and CTNNB1. CTNNB1 mutations co-occurred with EGFR mutations, akin to KIT and PDGFRA (p<0.05). The retrospective analysis indicated that the Optimus panel contributed to clinical management of patients in 56% of cases, with 85% detecting clinically relevant variants, aiding treatment definition in 74% of these cases. Conclusions: The Biomakers-developed Optimus panel empowers the molecular characterization of genomic and proteomic biomarkers across tumor types. Its significance in clinical practice lies in contribution to vital decision-making processes, particularly in treatment selection.
Characterization of Von Hippel Lindau gene variants by race.
Authors: Shao Yusra F. , Alloghbi Abdurahman , Kim Seongho , Al-Share Bayan A , Kokenakes Courtney , Heath Elisabeth I.
Published: June 2024

e15158

Background: Autosomal dominant (AD) pathogenic/ likely pathogenic (P/LP) variants in the VHL gene cause Von Hippel Lindau syndrome, historically studied in White populations. We aimed to characterize VHL variants and disease phenotypes in both Non-White (NW) patients, which include Asian and African-American (AA), and in Non-Hispanic White (NHW) patients. Methods: Patients undergoing germline genetic testing (GGT) at Invitae Corporation from November 2014 to March 2022, carrying a P/LP AD variant in VHL gene were identified. Demographic and clinical data were obtained from Test requisition forms. Fisher's exact test and Wilcoxon rank-sum tests were performed for categorical and continuous variables, respectively, to compare groups. Results: The final analysis included 363 patients (NW=27%). Hemangioblastoma was predominant in all groups (NHW=13%, NW=27%, p=0.004). Breast cancer exclusively occurred in NHW patients (7%, p=0.019). NHW and NW patients had a higher family history of breast cancer (NHW=7%, NW=1%, p=0.046) and hemangioblastoma (NHW=3%, NW=8%, p=0.037), respectively. Distribution of VHL variants between NW and NHW patients varied significantly (p<0.001, Indels p=0.009, substitution variants p<0.001). Deletion exon 2 was predominant in all groups (NHW=15%, NW=35%) P.Leu188Val was exclusive to NHW patients (26%)while p.Arg167Trp (NHW=6%, NW=11%) and p.Arg167Gln (NHW=2%, NW=10%) were more common in NW patients. Several unique variants in AA and Hispanic patients were seen. Conclusions: This study reveals differences in P/LP VHL variant distribution and disease phenotype between NHW and NW races. Ethnicity-specific characterization uncovers unique variants in AA and Hispanic patients. This dataset informs future research on VHL disease and treatment in diverse populations.
Establishing optimized staining protocol and cutoff values of pan-TRK immunohistochemistry for detecting NTRK fusions in solid tumors: A Chinese multicenter cross-sectional study.
Authors: Wu Shafei , Han Yuchen , Zhang Zhihong , Chen Gang , Wang Jian , Yang Wentao , Meng Bin , Sun Yan , Liu Yang , Li Wencai , Li Shenglei , Wang Lifeng , Zhang Hongying , Guo Lingchuan , Liu Yueping , Liu Xiaoding , Hong Ruping , Li Kaimi , Liang Zhiyong
Published: June 2024

e15160

Background: Using IHC to screen NTRK+ patients, followed by NGS confirmation, is a strategy recommended by ESMO guidelines. However, the current IHC staining protocol (Protocol) and cutoff value (CV) are suboptimal, resulting in limited screening performance. This study aims to optimize the Protocol and redefine the CV to improve the efficacy of pan-TRK IHC in screening NTRK fusions. Methods: 126 NTRK+ and 162 NTRK- solid tumor samples (spls), previously confirmed by NGS and/or FISH, were collected retrospectively from 12 hospitals across China in 2023. All spls were stained with VENTANA pan-TRK IHC assay by using two different Protocols: 1) the conventional one recommended by the manufacturer's instruction and 2) an amplification one that included additional amplification steps to enhance the staining. The IHC stained spls were interpreted based on the manufacturer's instruction, and the results were analyzed to calculate the CVs. The sensitivity, specificity, accuracy, PPV, and NPV based on these CVs and the CV reported in the literature were calculated. Results: 126 NTRK+ spls involve 25 fusion-partner types and 23 tumor types. IHC showed 35 NTRK- spls without staining, and 253 spls (126NTRK+/127NTRK-) stained. The staining predominantly localized to the cytoplasm and nucleus (132 cytoplasmic positive, 105 cytoplasmic and nuclear positive). Due to the limited samples with membrane staining, only CVs for cytoplasmic and nuclear staining were defined. In order to enhance the sensitivity and feasibility of the pan-TRK IHC assay in NTRK+ screening, the statistically calculated CVs were adjusted, and we recommended using the following CVs in clinical practice: 1) ≥1 intensity of cytoplasmic staining in ≥50% of tumor cells and/or 2) ≥1 intensity of nuclear staining in any percentage of tumor cells. Compared with the statistically calculated CVs, although the accuracy of the recommended CVs was slightly reduced (87.5% vs 93.75%), the sensitivity was improved (94.44% vs 89.68%). The sensitivity and specificity of the recommended CVs were higher than that of the previously reported CV (≥1%): sensitivity (94.44% vs. 87.9%) and specificity (82.1% vs. 81.1%). Conclusions: The pan-TRK IHC assay demonstrated high sensitivity while maintaining good specificity and accuracy, improving screening and enrichment efficacy for identifying NTRK fusions in solid tumors by utilizing the amplification protocol and the recommended CVs. Clinical trial information: ChiCTR2200066850 . [Table: see text]
Experience of personalizing cancer treatment in economically-constrained and resource-restricted community oncology practice in India through cost-effective broad spectrum NGS and survival outcomes: An observational study of 3 years.
Authors: Maheshwari Udip , Morzaria Dr Disha , Maniar Vashishth , Joshi Ashish , Bose Chirantan , Jobanputra Kunal , Shivchhand Akshay , Dave Ritu , Kalaskar Pritam , Pethe Chandrashekhar , Joshi Kshitij , Kendre Pradip
Published: June 2024

e15173

Background: NGS based mutational findings are increasingly used in oncology practice to personalize treatment strategies. We elucidate the impact of comprehensive genomic profiling and the new avenues it opens for personalized precision medicine. Methods: This was a retrospective study evaluating patients who underwent a cost-effective (<US $1000), inhouse developed comprehensive NGS test. Descriptive data was tabulated & mutational distribution, therapeutic strategies and survival outcomes were evaluated. Results: A total of 336 patients were evaluated from a community oncology practice over the last 3 years in Western India. The mean age was 59.2 years; with F:M being 1.04:1 and stage distribution being 3.5%, 5.9%, 9.5% and 80.9% for Stage I, II, III and IV respectively. Comprehensive NGS was performed to evaluate SNVs, CNVs, and indels spanning across over 15000 loci for 1080 tumor specific genes wherein 71.7% were tissue-based, 24.4% were liquid biopsy-based and 3.8% were combined tissue-DNA and ctDNA-based analysis. Majority (69.9%) of the patients were pre-treated while 30% were therapy naïve. The most common cancers evaluated were Lung (18.1%), Pancreatobiliary (15.1%), Breast (11.3%), Gynaec (9.5%), and Lower GI (9.5%). Pathogenic mutations were reported in 83.6% of the cohort while in 16.3% no mutations were detected. Most common mutations observed in this retrospective study were TP53 (38.3%), KRAS (16.6%), PIK3CA (9.5%), EGFR (7.4%) and PTEN (5.6%); and the distribution was largely similar in untreated as well as pre-treated cohorts. Furthermore, genomic alterations for each cancer type are described in Table 1. MSI high and TMB high (>10) were reported in 0.5% and 7.4% respectively. PDL1 positive IHC was reported in 3.2% of tissue samples, whereas HRD high (>50) was reported in 2.3% of the cohort of which the majority (11.5%) were from Upper GI tumors. Targetable genomic alterations were detected in 53.8% (181/336) of which 38.1%(69/181) received the suggested targeted therapy. Clinical response was seen as PR in 14.4% and CR in 2.8% of patients. Of 336 patients 4.76% received modified therapeutic regimens which differed from the standard of care, wherein median PFS was 8 mo [CI 95% (5.3-10.7)] while median OS was 55.1 mo [CI 95% (25.8-NA)]. Conclusions: This observational study outlines the potential benefit of personalizing treatment regimens in the management of solid organ cancers, especially in scenarios where standard-of-care regimens may have failed and the need to incorporate broad-spectrum NGS. [Table: see text]