bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biodegradable nanoparticles inhibit tumor growth by altering tumor-associated macrophages and cancer-associated fibroblasts.
Authors: Murthy Tushar , Podojil Joseph , Kwak Taekyoung , Vonteddu Prashanthi , Elhofy Adam , Boyne Michael , Puisis John , Veglia Filippo , Singh Surya , Dotiwala Farokh , Montaner Luis , Gabrilovich Dmitry , Donthireddy Laxminarsimha , Eraslan Rukiye-Nazan 
Published: June 2022

e14553 Background: The tumor microenvironment (TME) plays a crucial role in tumor growth and progression and has a significant influence on response to therapy. The TME consists of myeloid-derived cells, stroma (e.g. fibroblasts and extracellular matrix (ECM)), and the vasculature that together support tumor growth and progression. Studies in animal models and in humans show that myeloid- derived cells such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) engage in activities that support tumor growth and progression. These cells also promote immune suppression in the TME that blunts the efficacy of the anti-cancer drugs and immune-targeted therapies such as immune checkpoint inhibitors. In addition to MDSCs, cancer-associated fibroblasts (CAFs) in the TME support tumor progression via production of pro-tumor and pro-angiogenic growth-factors, remodeling of the ECM via production of proteases, and suppression of anti-tumor immune function. CAF abundance in the TME is a negative prognostic factor for several solid tumors and is associated with negative outcomes and poor response to immune-targeted therapies like immune checkpoint inhibitors. ONP-302 nanoparticles fabricated from biodegradable poly (lactic-co-glycolic acid)(PLGA) polymer have been previously described in the literature for the treatment of acute inflammatory conditions via immuno-modulatory effects on myeloid derived cells. Here, we evaluated the efficacy of ONP-302 nanoparticles at inhibiting tumor growth via targeted inhibition of myeloid-derived cells and reshaping of the TME. Methods: ONP-302 anti-tumor efficacy was evaluated in syngeneic mouse tumor models using both immunocompetent and immunodeficient mice. We examined the effect of ONP-302 treatment tumor growth kinetics and effects on the major cellular constituents of the TME such as myeloid-derived cells and CAFs. Results: Therapeutic treatment with ONP-302 in vivo resulted in a marked delay in tumor growth in three different syngeneic tumor models in immunocompetent mice. ONP- 302 efficacy persisted with depletion of CD8+ T cells in immunocompetent mice and also was effective in immune deficient mice. We found ONP-302 treatment caused a gene expression shift in TAMs toward the pro-inflammatory M1 type and substantially inhibited the expression of genes associated with the pro-tumorigenic function of CAFs. ONP-302 also induced apoptosis in CAFs in the TME. Conclusions: Our data indicate that the slowing of tumor growth after ONP-302 treatment is due to disruptions in known signaling pathways involving TAMs and CAFs, pathways typically supporting tumor growth. These data taken in concert indicate the activity of ONP-302 is pleotropic and affects multiple pathways.
Safety and efficacy of YBL-006, an anti-PD-1 monoclonal antibody in advanced solid tumors: A phase I study.
Authors: Oh Do-Youn , Park John J. , Lee Keun Wook , Kim Seung Tae , Sriuranpong Virote , Rha Sun Young , Yoo Changhoon , Keam Bhumsuk , Sabanathan Dhanusha , Kim Se Hyun , Park Joon Oh , Parinyanitikul Napa , Kim Min Hwan , Kim Kyu-Pyo , Kim Myungsuk , Yoon Jaebong , Lee Han Seung , Ock Chan-Young 
Published: June 2022

e14557 Background: YBL-006 is a fully human anti-programmed death-1 (PD-1) antibody under evaluating its safety and efficacy in phase I clinical trial. We have reported interim analysis of dose escalation cohort which showed a tolerable safety profile. Here, we present the updated clinical activity of YBL-006 in dose escalation and expansion cohorts. Methods: Dose escalation (0.5, 2, 5, 10 mg/kg) and dose expansion (flat doses of 200 mg every 2 weeks [Q2W] and 300 mg every 3 weeks [Q3W]) cohorts explored the safety, pharmacokinetics (PK) and objective response rate (ORR) in the patients with advanced solid tumors who failed or were ineligible to the standard of care. Adverse events (AEs) were graded using the CTCAE v5. ORR was assessed using the RECIST (v1.1). Lunit SCOPE IO, an H&E analysis tool, was applied as an exploratory biomarker, and samples with “Immune inflamed phenotype” were defined as those with high intratumoral TIL density in ≥ 20% of the tumor microenvironment. The cut-off date for analysis was Jan 4th, 2022. Results: A total of 67 patients (safety set) with advanced solid tumors were enrolled in the study. Median follow-up duration of the safety set was 1.6 months (range 0.2-16.8). There was no dose-limiting toxicity during dose escalation phase. Most frequent AEs were grade 1 or 2; fatigue (19.4%), pruritus (10.4%), and fever (7.5%), and two hypothyroidism (3.0%), one pneumonitis (1.5%), and one cytokine-releasing syndrome (1.5%) were observed. One subject experienced grade 3 diarrhea in the safety set. PK study showed that half-life was 8.0 days, and mean Cmax and AUC0-inf were 4.15 x 104 ng/ml and 1.12 x 107 ng/ml*h for 200 mg dose, and 6.26 x 104 ng/ml and 1.53 x 107 ng/ml*h for 300 mg dose, respectively. A total of 52 patients were evaluable for efficacy. ORR was 15.4%, including 1 complete response (penile squamous cell carcinoma [SqCC]), and 7 partial responses (two gastric adenocarcinomas, anal SqCC, paranasal sinus SqCC, nasopharyngeal carcinoma, neuroendocrine carcinoma, and thyroid Hurthle cell carcinoma). Durable responses were seen in 2 patients for over 12 months. Median duration of response was 4.9 weeks (range 1-65). Among efficacy set, 32 samples were available for Lunit SCOPE IO. ORR was significantly higher in inflamed immune phenotype compared to non-inflamed samples (62.5% vs 8.3% p = 0.005). Conclusions: Interim analysis of phase I trial of YBL-006 shows a tolerable safety profile and clinical activity. Notable anti-tumor efficacy was observed in inflamed immune phenotype. Clinical trial information: NCT04450901.
A novel nomogram could predict prognosis for multiple cancer patients with primary resistance to immune checkpoint inhibitors.
Authors: Li Xuanzong , Fan Xinyu , Wang Linlin 
Published: June 2022

e14561 Background: Cancer patients with immune checkpoint inhibitors (ICIs) treatment often experience unique progression response patterns, accounting for the discordance of short-term and long-term benefits. Identifying the specific characteristics of different quality progression disease (PD) events can maximize the curative effect of ICIs and further improve the prognosis of the patients with immunotherapy. In this study, we established a neutrophil-to-lymphocyte ratio (NLR)-based nomogram model which could predict survival for NSCLC patients with primary resistance to ICIs. Methods: Univariate and multivariate Cox regression analysis were used to evaluate the ability of each parameter to predict overall survival (OS). The regression coefficients obtained in multivariate analysis were visualized in the form of a nomogram, thus a new nomogram and risk classification system were established. The discrimination ability of the new model was evaluated using area under the curve (AUC) in receiver operating characteristic curve (ROC) analysis. Survival curves were made by the Kaplan-Meier method and compared by the Log-rank test. Results: A total of 1235 patients with multiple cancer types who accepted at least one dose of ICIs treatment between 2015 and 2018 at Memorial Sloan Kettering Cancer Center were included in our study. Among them, 624 PD-patients (obtaining PD as their best response) were used to identify potential survival-related characteristics and build a nomogram model. Univariate and multivariate analysis demonstrated that pretreatment NLR, treatment lines and Eastern Cooperative Oncology Group performance status scores were independent prognostic factors and were included in the predictive model. The ROC curves implied the good discrimination ability of the predictive model with the AUC value for 1-year OS was 0.756. And, the calibration curves showed that the predicted value of the 1-year survival rate by the nomogram was in good agreement with the actual observed value of it. Based on the nomogram, we divided PD-patients into high-, med- and low-risk subgroups. The OS of cancer patients in three risk groups were accurately differentiated either in all PD-patients or PD-NSCLC-patients, but not in the patients who responded to ICIs. Importantly, the prognosis of the low-risk PD-patients was significantly better compared with the patients in med- and low-risk groups (P < 0.001). Moreover, in the PD-patients with NSCLC, similar results were also found that patients had a worse OS in the high-risk group (P < 0.001). Interestingly, in contrast to the results in PD-patients, a comparable OS between high-, med- and low-risk groups based on our model was verified in the patients who responded to ICIs. Conclusions: The pretreatment NLR-based nomogram could predict the prognosis for pan-cancer patients with primary resistance to ICIs treatment.
Response assessment and toxicity in patients treated with immune checkpoint inhibitors in solid tumors : A comprehensive cancer care center experience from India.
Authors: Mehta Prashant , Sushmitha Cheemala , Sood Siddarth , Anand Shekhar , Badola Amit , Raju Anisha , Gupta Raman 
Published: June 2022

e14562 Background: Checkpoint inhibitors are approved in various solid malignancies in either first-line or following progression on chemotherapy. These have shown good efficacy with low toxicity. However, there are very few studies from Indian centers. The purpose of the study was to assess the real world efficacy and toxicity in patients treated with Immunotherapy (IO) in various solid malignancies. Methods: The present study is a retrospective single-center hospital-based registry study that included 94 patients treated with immune checkpoint inhibitors in various solid malignancies from January 1, 2017 to December 31, 2020. The investigator assessed response at 3-months post-initiation of treatment has been reported. Patients who received less than two months of Immunotherapy were excluded in response analysis. Adverse events during IO were documented and graded using CTCAE (Common terminology criteria for adverse events), v.5.0. All statistical analysis was performed using Microsoft Excel 2016 and R software (Rx 64 version 3.6.2). Results: Sixty-nine patients who received more than 2 months of IO were assessed. Baseline characteristics of patients are listed in table 1. Lung cancer 29% (n= 27) Head and neck cancer 22% (n=21) and metastatic renal cell carcinoma 10% (n=9) were the common cancers where IO was given. Overall response rate at 3 months was 55% (n=38). Progressive disease and stable disease were seen in 39% (n=27) and 6% (n=5) patients respectively. The reported severe adverse events were pneumonitis, colitis, and hepatitis, with Grade 3 or more toxicities were in 7% (5/69) patients. Conclusions: IO was associated with clinical benefit and fewer toxic effects; however, increased treatment cost remains a significant concern in developing countries like India.[Table: see text]
Feasibility of next generation sequencing (NGS) from Uzbekistan: A preliminary data analysis.
Authors: Olimova Zilola Avazovna , Pendharkar Dinesh 
Published: June 2022

e14579 Background: Molecular testing has become an important part of management of cancer patents. Due to local nonavailability and financial constrains NGS is picking up slowly in Uzbekistan. An attempt was being made to see feasibility and analyze next generation sequencing data from local population. Here we report data from first such big analysis. Methods: 76 advanced cancer patients were enrolled and tissue samples were sent for NGS. The analysis were sent to the lab for performing FOUNDATIONONER CDx (F1CDx) - the NGS based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations(indels), and copy numbers alterations(CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability(MSI), tumor mutational burden(TMB), and for selected forms of ovarian cancer, loss of heterozygosity(LOH) score, using DNA isolated from formalin-fixed, paraffin-embedded(FFPE) tumor tissue specimens. Results: Out of 76 patients (35 male 41female) there were 15/76 lung cancer patients, 13/76- breast cancer, 12/76 - colorectal, 5/76 - ovarian and other malignancies. In cohort of lung cancer, the multiple gene abnormalities detected were - EGFR-5/15; ALK-3/15; ROS-0; KRAS-1/15; NRAS-0; BRAF-1/15; MET-1/15; NTRK-3/15. In breast cancer population - BRCA1 mutation was found in - 3/13; BRCA2 in 1/13; ERBB-3/13; and ESR-1/13. In group with colorectal cancer the gene abnormalities located were - BRAF-1/12; KRAS-7/12: G12D-1; G12V-1; G12C-1; NRAS-0; MSI-3/7; MMR: MLH-1; MSH2-2; MSH3-2; MSH6-2. In ovarian cancer findings included - BRCA1 in 0/5; BRCA2-1/5; PALB-1/5; CHEK-1/5; PARP1-1/5. The most frequent genetic alteration observed in the whole group was TP53 (50/76). Commonest hereditary gene alterations besides TP53 were seen in ATM gene -12/76. A large number of Variant of Unknown Significance were also recorded. Conclusions: It is feasible to perform NGS analysis using reference laboratories. There is population of patients, willing to undergo specialized tests. Actionable molecular data information can be collected and utilized for patient care. No unique markers could be found due to small sample size.
A bivalent Tim-3/PD-1 bispecific antibody for the treatment of PD-1 antibody resistant or refractory NSCLC.
Authors: Liu Jiajian , Luan Y. , Deng H. , Wang F. , Wang C. , Zhang Z. 
Published: June 2022

e14597 Background: Immune checkpoint inhibitors (ICI) PD-1/PD-L1 antibody are key drugs for the treatment of non-small cell lung cancer (NSCLC). Bispecific antibody is one of the strategies aimed at the clinical needs for NSCLC patients who are resistant to or refractory from ICI treatment. Tim-3, one of the next generation of ICB targets, is co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. Methods: A bivalent to both Tim-3 and PD-1 bispecific antibody (Bis5) was developed and is in Phase I clinical trials for NSCLC patients who are resistant to or refractory from PD-1 antibody treatment. Results: Bis5 showed affinity of 5-8 nM to both Tim-3 and PD-1. Moreover, Bis5 showed better cell activity than Tim-3 and PD-1 antibody combination to activated T cell as well as NK and DC. Bis5 showed 77%-88% tumor inhibition which is close to PD-1 antibody alone in MC38 model. Neither PD-1 antibody or PD-1 and Tim-3 antibody combination show any activity in CT26 model while Bis5 showed significant tumor inhibition activity and doubled the survival rate. The highest non-severe toxicity dose (HNSTD) was 200mpk in monkeys. ADA were 33.3% (2/6), 83.3% (5/6), and 0.0% (0/6) at doses of 2, 10, and 50 mpk, respectively. The T1/2 were 31.7-66.5 h for doses 2-50 mpk. Conclusions: A Phase I, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of Bis5 in patients with advanced and/or metastatic solid tumors has started. Seven cohorts (0.1, 0.3, 1, 3, 6, 10, 15 mg/kg) are planned to be enrolled sequentially in the dose escalation part. In the expansion part, a cohort group of 10 patients is planned for post PD-1 treated NSCLC as the second or third line treatment.
Ground-glass opacity showed response to immunotherapy in cancer patients.
Authors: Wu Fang , Hu Chunhong , Liu Xiaohan , Li Yizheng , Zeng Yue , He Liuer , Liu Junqi 
Published: June 2022

e14605 Background: Ground glass opacities (GGO) are lesions with hazy density on CT. Immune checkpoint inhibitors (ICIs) achieved a significant improvement in the treatment of early and advanced non-small lung cancer (NSCLC). It is unclear whether ICI therapy show efficacy on GGO lesions. Methods: As the largest diameter of most lesions was less than 10mm, the definition of evaluable lesion we expanded the lower limit of the diameter to 4 mm. We retrospectively assessed cancer patients with GGOs who underwent at least two courses of immunotherapy between January 2016 and June 2021 in Second Xiangya hospital, China. Also, we evaluated GGOs that had been examined by low-dose thin-slice CT more than twice. Wilcoxon test was used to evaluate the length and diameter changes of GGO. We assessed the correlation between CT imaging features of GGO and the efficacy of immunotherapy through univariate and multivariate logistic regression. Results: Among eligible patients (n = 51), 35 were lung cancer patients and 16 were other tumor patients. Confirmed 95 GGOs were included. 68 GGOs were from lung cancer patients and 27 GGOs were from patients with other types of cancer (such as esophageal carcinoma, oral squamous cell carcinoma and hepatocarcinoma etc.). The diameter of GGO decreased significantly after immunotherapy (7.56 vs 4.31, P = 0.000). The same results were observed in lung cancer patients (7.98mm vs 4.92mm, P = 0.000) and in non-lung cancer patients (6.90mm vs 3.35mm, P = 0.001). The volume of GGO shirked significantly after immunotherapy in cancer patients (297.35mm3 vs 125.46mm3, P = 0.000) lung cancer patients (401.41 mm3 vs 164.91 mm3, P = 0.007) and non-lung cancer patients (137.93mm3 vs 65.04mm3, P = 0.000). Conclusions: GGO can response to immunotherapy, which indicates immunotherapy maybe potentially helpful for patients with multiple GGO lesions such as multiple primary lung cancer (MPLC) patients.
A phase 2 study of anlotinib in patients with metastatic pheochromocytoma/paraganglioma.
Authors: Tong Anli , Cui YunYing , Gao Yinjie , Cheng Yuejuan , Li Yuxiu 
Published: June 2022

e15000 Background: Metastatic pheochromocytoma / paraganglioma (MPP) are rare while the prognosis was poor and the efficacy for current therapy was unsatisfactory. Anlotinib is a multikinase inhibitor targeting tumor angiogenesis and growth. Currently, there is no study evaluating the efficacy and safety of anlotinib in MPP pts. Methods: This is a prospective, single-arm phase 2 trial (NCT 04860700). Pts with histologically or radiologically confirmed MPP were enrolled. Main other inclusion criteria were 18-75 years old and ECOG PS 0-2. Anlotinib (8-12mg, QD) were given orally from d1 to d14 every 21 days until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included biochemical (catecholamine levels) response rate (BRR), progression-free survival (PFS) and safety. Results: 10 pts with MPP were enrolled and tumor response were evaluated in 6 patients. All these 6 patients had objective radiological evidence of progression within 6 months before enrollment. Tumor shrinkage was observed in 4 pts, 1 achieved partial response (PR) and 3 achieved stable disease (SD). The ORR was 16.7% (1/6). For 1 patient (p-1) with no measurable lesions, the pathological lymph nodes shrunk obviously and the rapid progression of bone metastatic lesion was well controlled. Among all 6 pts, catecholamine levels were obviously decreased in 4 pts, achieving a BRR of 67%. 1 patient who developed blindness at right eye caused by the progression of intracranial metastasis after chemotherapy had recovered the vision after anlotinib treatment. At the data cutoff date on February 1st, 2022, 1 patient terminated anlotinib since obvious elevation of catecholamine level and others were still in treatment with no radiographic disease progression. The median treatment duration was 7.5 cycles. The details of efficacy result were listed in table below. Overall, treatment of anlotinib blocked the rapid disease progression and achieved a durable disease control. The most common treatment-related adverse event (TRAE) was hypertension (5/6), which was well controlled, other TRAEs occurred in > 1 pts included grade 1 or 2 proteinuria (2/6) and palmar-plantar erythrodysesthesia syndrome (2/6). Conclusions: The preliminary results of this study indicated that anlotinib is a potential choice for the treatment of MPP with the high ability on disease control and well tolerability. Clinical trial information: NCT04860700. [Table: see text]
Antitumor pharmacological activity of hybrid organotin compounds on the Lewis epidermoid carcinoma model.
Authors: Dodokhova Margarita Avdeevna , Kotieva Inga Movlievna , Safronenko Andrey Vladimirovich , Alkhuseyn-Kulyaginova Margarita Stefanovna , Kotieva Elizaveta Мikhailovna , Kotieva Violetta Мikhailovna , Starostin Sergey Igorevich , Nikitin Evgeniy Aleksandrovich , Shpakovsky Dmitriy Borisovich , Milaeva Elena Rudolfovna 
Published: June 2022

e15004 Background: New antitumor agents based on organic metal derivatives are intensively determined and created by now. Tin compounds are of great interest among them [Milaeva E.R.et al. Novel selective anticancer agents based on Sn and Au complexes. Pure & Applied Chemistry. 2020, 92, 1201-1216]. The results of studies on cell line models allowed us to conclude that cytotoxic effect of organotin compounds is pronounced, so it is advisable to hold their further studies on biological models in vivo [ Dodokhova M.A. et al. Pharmacotherapeutic potential’s evaluation of organotin compounds in vivo Biopharmaceutical journal, 13(3), 30 – 34 (2021); doi: 10.30906/2073-8099-2021-13-3-30-34]. For the specialists of experimental pharmacology and oncology is relevant to rate the antitumor activity of hybrid organotin compounds on experimental malignant tumors. Methods: The study was held on C57Bl/6 mice (females, n = 36, each cohort contained 12 mice) on a Lewis epidermoid carcinoma model (subcutaneous transplantation) [Kit O.I. et al. Influence of chronic neurogenic pain on the dynamics of the no-system functioning during melanoma B16/F10 growth in male mice. Siberian Journal of Oncology, 2021, 20(3), 67–75]. Bis-(3,5-di-tert-butyl-4-hydroxyphenyl)dimethyl tin(Me-3) and (3,5–di–tert–butyl–4–hydroxyphenylthiolate) triphenyl tin (Me-5) were used as chemotherapeutic agents. Groups of animals were formed as follows: I (experimental) - Me-3 at a dose of 75 mg / kg; II (experimental) - Me-5 at a dose of 50 mg / kg; III (control group) - without pharmacological substances. The doses were characterized as the most effective according to the results of a pharmacological activity screening study. The compounds were injected intraperitoneally daily for 5 days. All animals were euthanized since 21 days after the tumor cells transplantation. The antitumor effect was estimated by the percentage of tumor growth inhibition by weight (%). All manipulations were carried out in accordance with the European Convention for the Protection of Vertebrates Used for Experimental and Other Scientific Purposes (ETS 123). Results: After the intraperitoneal injection of chemical substances Me-3 and Me-5, there was revealed an inhibition of growth by weight of Lewis epidermoid carcinoma’s primary node for all experimental groups, 23.7% and 28% respectively. Conclusions: The injection of organotin compounds with different ligand groups allows us to suggest a biocidal activity of the organotin component on the primary tumor node cells.