bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II safety and preliminary efficacy of PM1022, a bispecific antibody targeting PD-L1 and TIGIT, in patients with advanced solid tumors.
Authors: Xue Junli , Zhang Yan , Hu Xudong , Zhao Wei , Sun Yuping , Li Qun , Jin Xiaoying , Xue Liqiong , Ge Xiaoxiao , Lin Fengjuan , Tang Wenbo , Zhou Jiuli , Guo Ye 
Published: June 2024

e14694 Background: PM1022 is an anti-PD-L1 × TIGIT bispecific antibody that is engineered with a fully human IgG targeting TIGIT in an IgG1 wild type Fc backbone, fused to a VHH at the c-terminus targeting PD-L1. The potential MOA includes releasing T cell inhibition by blocking both the PD-L1/PD-1 and CD155/CD112/TIGIT pathways, as well as depleting Treg cells in the tumor microenvironment and engaging FcγRs to activate myeloid cells. PM1022 showed robust in vitro and in vivo efficacy in preclinical studies, and this is the first in human study. Methods: This phase Ⅰ/Ⅱ study consists of a standard 3+3 dose escalation and dose expansion part. PM1022 was administered intravenously as monotherapy on Day 1 of 21-day cycle. The primary objectives were to assess safety, tolerability and pharmacokinetics in patients with advanced solid tumors. Results: As of January 28, 2024, a total of 15 patients in dose escalation part have received at least 1 dose of PM1022, with 3 patients in each of the 100, 200, 400, 800 and 1200 mg dose levels respectively. No DLT was observed up to 1200 mg. Of the 15 patients, TRAEs occurred in 8 patients (53.3%), ≥ Grade 3 TRAEs occurred in 1 patient with platelet count decreased. No patients were discontinued from PM1022 due to TRAE. The most common TRAEs were rash (20%) and aspartate transaminase increased (20%). 14 patients completed at least one tumor evaluation. The median duration of PM1022 exposure was 6.1 weeks (range, 5.0-48.0 weeks). The ORR per RECIST 1.1 was 7.1% with a DCR of 35.7%. Preliminary antitumor activity has been observed in 1 patient with NSCLC (1200 mg, still on treatment) with previous PD-L1 TPS 100% who was enrolled after previous 3 lines therapy, including chemotherapy and anti-PD-1 treatment, and had a partial response in target lesion with 56.8% reduction. Another patient with esophageal cancer had been on PM1022 for total of 48 weeks until initiation of new anti-cancer therapy. Pharmacokinetics were dose-proportional with a terminal half-life of 7-13 days across the dose range of 100-1200 mg. Conclusions: PM1022 was safe and well-tolerated up to 1200 mg Q3W with preliminary anti-tumor activity. These findings could support further exploration of PM1022 in advanced solid tumors. Clinical trial information: NCT05867771 .
Using exponential decay to model survival curves in immunotherapy trials.
Authors: Opperman Tarquin Dean , Stewart David J. , Nasser Abdullah 
Published: June 2024

e14698 Background: In oncology trials, survival outcomes, specifically overall survival (OS) and progression-free survival (PFS), are commonly assessed using the Kaplan–Meier estimator. Survival curves in immunotherapy trials for advanced solid tumors frequently display first-order kinetics, suitable for exponential decay modeling. This study utilizes such models on early trial data to predict median OS and PFS, aiming to yield earlier actionable insights. Methods: we searched PubMed to identify immunotherapy trials focusing on advanced solid tumors. Survival curves, along with actual OS and PFS data, were extracted and segmented into immunotherapy and control groups. An exponential decay model was fitted to the initial quartile of events, from which median OS and PFS were extrapolated. These forecasts were then benchmarked against documented trial results. Results: Our analysis included 347 subsets from 122 immunotherapy trials. We observed strong correlation coefficients between actual and predicted OS (0.882 for the immunotherapy group, 0.784 for the control group) and PFS (0.746 for the immunotherapy group, 0.791 for the control group). The predictive models were formulated as follows: Immunotherapy: OS = 0.867 × predicted OS (pOS) + 2.623 ⋅ Control: OS = 0.623 × pOS + 3.731; and Immunotherapy: PFS = 0.583 × predicted PFS (pPFS) + 1.827 ⋅ Control: PFS = 0.519 × pPFS + 1.901. Conclusions: The notable correlation between the actual and predicted survival outcomes supports the efficacy of exponential decay models in forecasting median OS and PFS from preliminary trial data. The consistency observed across trials underscores the model's potential as a predictive tool in clinical research. Further prospective studies are warranted to validate these predictive models and explore their implications for trial design and therapeutic decision-making in oncology.
Discovery of HDM2010, a highly potent PTPN2 inhibitor for immunotherapy.
Authors: Li Ke , Min Chen , Zhang Zhiping , Liu Dongzhou 
Published: June 2024

e15021 Background: Protein tyrosine phosphatase non-receptor type 2 (PTPN2), a negative regulator of JAK–STAT pathways that plays a crucial role in the immune system, has been identified as a promising target for immunotherapy. Genetic deletion of PTPN2 in either tumor cells or host immune cells promotes the anti-tumor immunity. In addition, PTPN2 inhibitors, alone or in combination with anti-PD1 therapy, significantly reduced tumor growth and enhanced survival in several subcutaneous tumour models. These findings demonstrate that PTPN2 inhibitors may have clinical benefits for immunotherapy-resistant tumors. Herein, the discovery of a series of novel PTPN2 inhibitors and their implications for immunotherapy are reported. Methods: We have successfully developed a series of small molecule inhibitors that specifically target PTPN2/N1. Molecular design was based on a novel backbone and incorporating both structure-based drug design (SBDD) and computational chemistry techniques. To evaluate the efficacy of our inhibitors, PTPN2 phosphatase activity was monitored using the small-molecule substrate DiFMUP in a fluorescence assay format in vitro. Tumor cells were treated with IFNγ and the cell viability was measured. Pharmacokinetic studies were conducted in mice, with serial blood samples analyzed by liquid chromatography−mass spectrometry (LC−MS)/MS. Pharmacokinetic parameters were calculated by noncompartmental analysis. Results: Based on the co-crystal structure of this target reported and multiple previous research projects, we have designed a multitude of novel compounds with the employment of computer-aided drug design (CADD) and scaffold hopping. Through a comprehensive evaluation of the in vitro and in vivo parameters, we have identified a series of compounds displaying potent PTPN2 inhibition (IC50 < 10 nM). Moreover, the compounds displayed remarkable efficacy in killing tumor cells to IFNγ treatment (IC50 < 100 nM). Artificial intelligence was utilized to conduct assessment and prediction of ADME properties, improving the drug-ability including permeability and physicochemical properties. Currently, a series of compounds demonstrating outstanding potency and good pharmacokinetic profiles, with lower hERG blockage (hERG IC50 > 30 µM), were synthesized and characterized. Among these hit compounds, a leading compound with PTPN2 IC50 = 1.1 nM and tumor cells IC50 = 79.5 nM was identified for further optimization and evaluation. Conclusions: We reported our work on discovering HDM2010, in which a series of potent PTPN2 inhibitors with prominent PK and safety profile were synthesized and characterized. Further optimization including in vivo experiments will lead to a preclinical candidate (PCC) selection.
YB-800, a monoclonal antibody targeting the human neuronal pentraxin receptor (NPTXR), as a potential candidate for the design of a first in class antibody drug conjugate (ADC) as novel therapeutic intervention in gastro-intestinal cancers.
Authors: Janicot Michel , Wennemuth Gunther , Lyndin Mykola , Moyer Janine , Schiemann Peter 
Published: June 2024

e15022 Background: The human neuronal pentraxin receptor (NPTXR) gene encodes a type II transmembrane protein that functions as a trans-synaptic organizer and anchors neuronal pentraxin complexes to plasma membranes. Beside a subset of neuronal cells (Hippocampus and Cerebral Cortex), expression of NPTXR is not detected in all other tissues [ The Human Protein Atlas database]. In recent studies [Kanda et al. (2020) Mol. Cancer. doi: 10.1186/s12943-020-01251-0], transcriptome and bioinformatics analysis of gastric cancer (GC) tissues from patients with or without metastasis have revealed that NPTXR expression was associated with disease progression. NPTXR expression was also correlated negatively with survival in GC patients. It appears that NPTXR does not have a major physiological function; e.g., NPTXR−/− mice showed no abnormalities in reproduction, development, metabolism, or motor function. NPTXR is expressed in a number of GI cancers, i.e., gastric, esophageal, colorectal, pancreatic, bladder, liver, as well as breast and thyroid cancer. YB-800 is a fully humanized monoclonal antibody against NPTXR (identified by in silico analysis). Methods: The present studies were conducted to provide a rationale for the design of a YB-800-based antibody drug conjugate (ADC) for therapeutic intervention in oncology. Hence, YB-800 binding to and internalization in selected tumor cells, as well as immunohistochemistry (IHC) in tumor biopsies, were evaluated. Results: Taken together experimental data confirm that: (i) YB-800 binds to a new target (NPTXR) on selected tumor cells; confirmed by FACS analysis; (ii) IHC analysis in tumor samples demonstrates specific immunoreaction in bladder, gastric, prostate, hepatocellular carcinoma, colorectal cancer and cervical cancer, but not in adjacent healthy tissues; and (iii) once YB-800 binds to NPTXR, the conjugate is internalized in selected tumor cells in a time-dependent manner. Conclusions: In conclusion, YB-800 represents a first in class ADC candidate that could be used as novel treatment for gastro-intestinal cancers. Hence, as initial proof of concept, tesirine (DNA intercalating agent) and deruxtecan (topoisomerase I inhibitor) containing protease-sensitive linkers were coupled to YB-800 by stochastic maleimide conjugations to interchain cysteines. Initial results with YB-800-based ADCs will be discussed.
Molecular profiling using next generation sequencing with high-purity enrichment of circulating tumor cells.
Authors: Choi Jaesung , Jeong Aejin , Park Sehwan , Kim Hanbyeol , Pak Sehyung , Song Min-Ji , Kim Jungwon , Lee Hai-Chon 
Published: June 2024

e15054 Background: In the field of liquid biopsy, coupled with next generation sequencing (NGS), circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) can serve as an alternative substrate to tumor tissue for mutation detection and companion diagnostic purpose. Emerging evidence suggests that complementary sequential CTCs and ctDNA profiling offers promising benefits for prognosis and treatment. In contrast to well-established ctDNA extraction methods, the process of isolation of intact CTCs for NGS analysis has not yet been fully elucidated. Here we show that isolation and harvesting of viable CTCs using CytoGen's Smart Biopsy™ System achieves high CTC purity for NGS analysis in breast cancer and non-small cell lung cancer (NSCLC). Methods: Targeted panel sequencing for CTC was developed to detect representative mutated genes using the Oncomine™ Comprehensive Assay Plus (501 genes) and the Oncomine™ Pan-Cancer Cell-Free Assay (52 genes). Analytical validation was performed with breast cancer cells MDA-MB-231 (50 to 5 cells) and NSCLC cells H358 (10 and 5 cells) which were spiked into 5 mL of healthy blood to mimic CTCs. CytoGen's Smart Biopsy™ System was applied to isolate the CTCs. Subsequently, CD45 depletion and whole genome amplification were performed. Sequencing was performed on Ion S5™ XL Systems using an Ion 550™ chip kit. The sequencing data were then analyzed using the Ion Torrent software with the default configurations. Results: As a result of targeted panel sequencing with Oncomine™ Comprehensive Assay Plus, representative breast cancer mutation genes (BRAF, KRAS, TP53, NF2 and NOTCH3) were detected in at least 20 MDA-MB-231 cells. In the results using Oncomine™ Pan-Cancer Cell-Free Assay, mutated genes (BRAF, KRAS and TP53) were successfully detected in as few as 5 MDA-MB-231 cells and, in addition, KRAS mutation was detected even with only 5 H358 cells. These results suggest that CytoGen's Smart Biopsy™ System could be applied to detect representative mutated genes in clinical breast cancer and NSCLC patient samples with detection technology that require high sensitivity and specificity. Conclusions: Molecular analysis of CTCs is a challenge since CTCs are very rare in the blood and there are technical limitations in isolating CTCs with sufficient purity for NGS analysis. In this study, we developed the process for NGS analysis on very small number of high-purity CTCs using CytoGen's Smart Biopsy™ System. Taken together with the results from our ongoing clinical trials, this process could provide information for the diagnosis and appropriate treatment of breast cancer and NSCLC patients.
A phase 1 study of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated (TAA) CD8+T cells in patients with advanced solid tumors.
Authors: Yu Xianjun , Zhang Jian , Liu Jiajian 
Published: June 2024

e15074 Background: PD-1/PD-L1-targeted immunotherapies have become critical in the treatment for many tumors. However, there has been limited progress in low immunogenic cancers such as pancreatic ductal adenocarcinoma (PDAC) or CRC. LB4330 is a novel, bi-functional molecule targeting Claudin18.2 and IL-10 with high affinity anti-CLDN18.2 (14pM). It may activate TAA CD8+ T cells in the tumor microenvironment (TME) and has potential alone or in combination with immunotherapeutic agents, including PD-1/PD-L1 mAbs, for the treatment of advanced solid tumors. A FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001) is ongoing in China. Methods: Eligible patients were ≥ 18 years old with ECOG PS 0-1. Dose cohorts ranged from 0.001 mg/kg to1 mg/kg IV QW: 0.001mg/kg-0.05mg/kg in an accelerated titration design, and 0.2mg/kg-1 mg/kg using traditional 3+3 design. The primary objective is safety, including dose-limiting toxicities (DLTs). The secondary/exploratory objectives include efficacy, pharmacokinetics (PK), and immunogenicity. Results: As of January 5, 2024, 30 patients with advanced solid tumors who have failed standard treatments or who did not have standard treatments available or applicable at this stage were recruited, including 17 PDAC, 6 GC, 3 CRC and 4 other solid tumor patients. All patients enrolled had multiple organ metastases. Treatment emergent AEs (TEAEs) occurred in 90.3% of patients. The most common Treatment related AEs (TRAE) were thrombocytopenia, anemia, fever, rash/itching, and fatigue. 7 patients (23.3%) had grade 3 TRAE which were infusion reaction, skin itching, rash, fever, abdominal distension, anemia, and thrombocytopenia. 1 patient (3.2%) had grade 4 AE, thrombocytopenia. On-treatment scan for efficacy was available for 20 patients, and 7 had stable disease. Target lesion shrinkage was observed in 2 pts, including one PDAC patient whose sum of target lesion reduced by 32.9% from baseline. PK was generally dose proportional, with t½ ~2 days. The immune activating Th1 cytokine IL-18 was elevated in 77.8% of patients treated with LB4330. Updated data will be presented. Conclusions: LB4330 has manageable safety and shows preliminary efficacy at tolerable doses. Dose and efficacy expansion study is ongoing in more PDACs and other solid tumors. In the meantime, Phase I study of LB4330 in combination with PD1/TIM-3 bispecific antibody LB1410 has been initiated in different tumor types as well. Clinical trial information: NCT05707676 .
Use of integrated multi-omics analysis to determine antitumor efficacy of donafenib in combination with FADS2 inhibition in hepatocellular carcinoma.
Authors: Li Hui , Wu Di , Dai Yafeng , Gao Song , Guo Jianhai , Zhang Pengjun , Kou Fuxin , Liu Shaoxing , Feng Aiwei , Liu Baojiang , Zhu Xu 
Published: June 2024

e15083 Background: Pharmacotherapy remains a pivotal treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Donafenib, globally the first targeted therapy proven to offer superior survival benefits and safety over sorafenib in a large-scale phase III clinical trial with head-to-head comparison, has been adopted for first-line treatment of advanced HCC. Given the limited basic research on Donafenib both domestically and internationally, and its constrained clinical efficacy, this study aims to explore combination drug therapy for HCC in an attempt to achieve further breakthroughs and enhance the anticancer activity of Donafenib. Methods: A xenograft tumor model in nude mice was established to observe the in vivo antitumor effects of Donafenib. Transcriptomics and proteomics were employed to characterize the gene expression changes in HCC cell lines after Donafenib intervention and to screen for key molecules. A series of assays, including the Cell Counting Kit-8 (CCK8), flow cytometry, scratch assays, Transwell assays, Western blotting, and in vivo tumorigenicity in nude mice, were conducted to determine the impact of the hub gene on the malignant behavior of HCC and to evaluate the combined antitumor effects of the molecular inhibition and Donafenib treatment in HCC. Results: Treatment with Donafenib significantly slowed tumor growth in a nude mouse xenograft model, resulting in a marked reduction in final tumor volumes compared to control subjects. Proteomic analyses post-Donafenib treatment identified FADS2 as the protein with the highest absolute log2 fold change among all differentially expressed proteins in HCC cells. This finding was corroborated by transcriptomic data, which indicated a concurrent downregulation of FADS2 at the mRNA level. Subsequent in vitro and in vivo assays validated the inhibitory effect of FADS2 blockade on the malignant biological behaviors of HCC cells. Importantly, the concomitant administration of Donafenib and the FADS2 inhibitor SC-26196 exhibited a synergistic antitumor action, significantly enhancing therapeutic efficacy in both HCC cell lines and xenografted tumors in nude mice. Conclusions: Combination therapy, a prevalent approach in clinical oncology, has the potential to augment treatment efficacy while simultaneously diminishing toxicity. This study employed an extensive multi-omics approach complemented by a range of both in vitro and in vivo experiments. It revealed that the synergistic use of Donafenib and SC-26196 markedly enhances Donafenib-induced the inhibition of cancer cell growth and metastasis, demonstrating a significant synergistic antitumor effect. These findings from our preclinical investigations may offer a promising new combinational drug regimen for the therapeutic management of HCC patients.
Effect of DeltaRex-G ± DeltaRex-G Plus (an FDA-approved drug) on advanced chemoresistant pancreatic cancer, sarcoma, and breast cancer.
Authors: Chawla Neal Shiv , Jeffrey Samantha , Omelchenko Nadezhda , Carter Rheanna , Agarwal Anmol Dia , Buhyian Ishrat , Isacoff William H. , Morse Michael , Swaney William , Chawla Sant P. , Hall Frederick L. , Gordon Erlinda Maria 
Published: June 2024

e15086 Background: Expanded access for DeltaRex-G, a tumor targeted retrovector encoding a CCNG1 inhibitor, is being studied for advanced cancers. Methods: 137 archived tumor specimens were analyzed with AI RNA sequencing to identify CCNG1 expression levels, reported as: Low = 17%, Medium-low = 17%-49%, Medium-high = 50%-83%, High = 83%. Nine patients with advanced solid malignancies, whose CCNG1 levels were identified, received DeltaRex-G (2-3 x 10e11 cfu/dose one to three times a week), either without an FDA-approved drug, or with an FDA-approved drug (“DeltaRex-G Plus”). Overall survival, duration of treatment, and responses were evaluated. Results: All analyzed tumors showed enhanced CCNG1 expression. Thirty (22%) tumors exhibited High CCNG1 expression, 48 (35%) showed Medium-High CCNG1 expression, 53 (39%) displayed Medium-Low CCNG1 expression, and six (4%) had Low CCNG1 expression. One hundred (73%) patients had metastatic disease, and 37 (27%) had localized disease. There was no correlation between CCNG1 expression and disease stage. Four patients with advanced pancreatic cancer (n = 1), Stage 1 HR+Her2+ invasive breast cancer (n = 1), Stage 1 triple negative breast cancer (n = 1), and squamous cell carcinoma of skin (n = 1), received DeltaRex-G alone or DeltaRex-G Plus between 2008 and 2021 and are alive 15, 3, 2.5, and 2.5 years since treatment initiation, respectively. Retrospective analysis of their respective tumors showed CCNG1 expression levels of 24%, 23%, 74%, and 40%. Three of the patients are in sustained remission and the patient with squamous cell carcinoma had a partial response. Of the five patients currently being treated with DeltaRex-G Plus: one patient with advanced breast cancer had a partial response (n = 1), one patient with advanced pancreatic cancer (n = 1) and three patients with soft tissue sarcoma (n = 3) had stable disease. Four of five patients had previously progressed with standard doses of chemotherapy. All patients are alive from 11 to 22 weeks since treatment initiation. No serious treatment-related adverse events have been reported. Conclusions: Taken together, the data shows that (1) 100% of 137 tumors tested have enhanced CCNG1 expression, further reinforcing the 2021 FDA-CBER authorization for use of DeltaRex-Plus, and (2) DeltaRex-G Plus is a promising therapy for advanced pancreatic cancer, sarcoma, and breast cancer. Randomized Phase 2/3 studies are warranted to confirm the efficacy and safety of DeltaRex-G Plus. Clinical trial information: NCT04091295 .