bluuebunny/crossref_metadata_2025_split huggingface dataset:
14-gene immunoglobulin (IGG) and proliferation signatures and association with overall survival across cancer-types.
Authors: Schettini Francesco , Paré Laia , Marín-Aguilera Mercedes , Puig Susana , Mezquita Laura , Baste Neus , Pascual Tomás , Martinez Saez Olga , Conte Benedetta , Jares Pedro , Puig-Butillé Joan Anton , Sanfeliu Torres Esther , González-Farre Blanca , Villagrasa Patricia , Conte Pier Franco , Perou Charles , Parker Joel S. , Brasó Maristany Fara , Prat Aleix 
Published: June 2022

2636 Background: The HER2DX prognostic assay in early-stage HER2-positive breast cancer integrates clinical variables and 4 gene expression signatures (GES) tracking IGG, tumor proliferation, luminal cell differentiation, and the expression of the HER2 amplicon. Here, we assessed the prognostic value across cancer-types of each of these four individual GES and a research-based version of the HER2DX risk-score. Methods: RSEM batch normalized RNA-sequencing gene expression data from The Cancer Genome Atlas (TCGA) project were downloaded from cBioPortal. The association between a research-based version of the HER2DX risk-score, and each GES, with overall survival (OS) was assessed as continuous variables using univariate Cox regression model. The research-based version of the HER2DX risk-score tested did not include clinical variables. The Cox model was applied to estimate hazard ratios (HR) with 95% confidence intervals. The threshold for statistical significance was set at p< 0.05. Results: Gene expression data from 9,852 patients representing 30 different cancer-types were evaluated. The proliferation, IGG, luminal and HER2 amplicon GES were significantly associated with OS in 40.0%, 33.3%, 23.0% and 6.7% of the cancer-types tested, respectively. The IGG GES was found significantly associated with a favorable OS in breast cancer (HR: 0.73, p < 0.001), cervical and head & neck squamous cell carcinomas (HR: 0.75, p = 0.021 and HR: 0.78, p < 0.001), lung adenocarcinoma (HR: 0.84, p = 0.020), skin melanoma (HR: 0.73, p < 0.001) and sarcomas (HR: 0.78, p = 0.029). Conversely, association of IGG GES with unfavorable OS was observed in uveal melanoma (HR: 1.74, p = 0.008), kidney clear cell and papillary cell carcinomas (HR: 1.29, p < 0.001 and HR: 1.44, p = 0.017, respectively), as well as brain low-grade gliomas (LGG) (HR: 1.56, p < 0.001). Finally, the research-based HER2DX risk-score was found significantly associated with OS in 11 of 30 (36.7%) cancer-types, including breast (HR: 1.42, p < 0.001) cervical and head & neck squamous cells cancers (HR: 1.36, p = 0.018 and HR: 1.30, p < 0.001), lung adenocarcinoma (HR: 1.34, p < 0.001), skin melanoma (HR: 1.34, p < 0.001), sarcomas (HR: 1.41, p = 0.003), adrenocortical carcinoma (HR: 2.31, p < 0.001), endometrial carcinoma (HR: 1.36, p = 0.005), hepatocarcinoma (HR: 1.26, p = 0.012), LGG (HR: 1.37, p = 0.001) and mesothelioma (HR: 1.48, p = 0.005). Conclusions: The 14-gene IGG and proliferation signatures are strong prognostic biomarkers across cancer-types. The opposite association of IGG with OS depending on the cancer-type warrants further investigation.
Phase 1 dose escalation study of DSP107, a first-in-class CD47 and 4-1BB targeting multifunctional immune-recruitment protein, in patients with advanced solid tumors.
Authors: Luke Jason J. , Saeed Anwaar , Bashir Babar , Shwartz Yaffa , Tabakman Rinat , Foley-Comer Adam , Jimeno Antonio 
Published: June 2022

2647 Background: DSP107 is a bi-functional, trimeric, fusion protein composed of sequences from the extracellular domain of SIRPα and 4-1BBL. The SIRPα arm targets CD47 overexpressed on tumor cells, blocking the “don’t eat me” checkpoint and triggering tumor cell phagocytosis. The trimeric 4-1BBL arm, once cross-presented and immobilized by SIRPα binding to CD47, interacts with 4-1BB expressed on activated immune cells, mainly T- and NK cells in the tumor microenvironment, and stimulates their proliferation and activation. Thereby, DSP107 triggers both an innate and an adaptive immune response. Here we describe data from the completed DSP107 monotherapy dose escalation portion of study NCT04440735. Methods: Adult patients with advanced solid tumors were treated with weekly intravenous DSP107 infusions (0.01 - 10 mg/kg) during 3-week treatment cycles. An accelerated dose escalation in single patient cohorts (dose levels 1-3) was followed by a standard 3 + 3 design. The primary objective was to determine safety, tolerability and pharmacokinetic (PK) parameters. Paired biopsies were obtained from 8 patients (screening, after cycle 2). Restaging imaging was performed every two months and evaluated by RECIST criteria. Results: In 23 patients, DSP107 demonstrated no treatment related hematologic or hepatic adverse events (AEs) and no dose limiting toxicities. Grade 1-2 treatment related AEs were observed in 70% of patients (16/23). The most frequent AEs included infusion related reaction (IRR; 26%), diarrhea (17%), fatigue (17%), nausea (13%) and constipation (9%). IRRs were managed during subsequent infusions by reducing the infusion rate and administering IV fluids. No significant systemic cytokine release was measured at any dose level using a 10-plex, pro-inflammatory panel. PK analysis revealed 100% CD47 receptor engagement on peripheral T and NK cells at doses of 3 mg/kg and above. DSP107 did not bind CD47 on red blood cells at any dose. Preliminary histologic assessment of paired biopsies by an independent, blinded pathologist demonstrated increased tumor necrosis compared to screening in 3 out of 4 patients associated with immune cell infiltration. Immuno-profiling of tumor by immunofluorescence is on-going. Stable disease as best response was observed in 11/22 patients with treatment duration up to 26 weeks. Conclusions: DSP107 is a novel, CD47 and 4-1BB targeting fusion protein with a differentiated safety, binding and pharmacodynamic profile compared to other CD47 and 4-1BB targeting agents. Clinical trial information: NCT04440735.
A phase 1a dose-escalation study of PY314, a TREM2 (Triggering Receptor Expressed on Macrophages 2) targeting monoclonal antibody.
Authors: Patnaik Amita , Hamilton Erika P. , Winer Ira Seth , Tan Winston , Hubbard Joleen M. , Schenk Erin Lynn , Sonbol Mohamad B. , Jahchan Nadine , Pierce Kristen , Li Yunfeng , Reyno Len , Chamberlain Marc 
Published: June 2022

2648 Background: To characterize the safety and tolerability of PY314, an immunosuppressive macrophage depleting antibody, as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors including subject’s refractory to checkpoint inhibitors if approved for that indication. Methods: Two were evaluated in subjects with advanced solid tumors, single agent PY314 and PY314 in combination with 200 mg of pembrolizumab using a 3+3 dose escalation study design. Dosing was intravenous and administered once every 3-weeks, a defined cycle. Disease assessment by RECIST 1.1 was performed every 6 weeks. Each stratum included 4 dose levels of PY314 (1, 3, 10, and 20 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM2 expression by immunohistochemistry. Based on preclinical evaluation of TREM2 expression, HR+ HER2- and triple negative breast cancer, colorectal cancer, renal cell cancer, non-small cell lung cancer and gynecologic cancers were studied. Results: 28 subjects (median age 60 years [range 26-76], 22 females and 6 ) with an ECOG PS <2 were enrolled and all, but one was (1 subject withdrew consent after dosing). 15 subjects were treated with single agent PY314 and 13 were treated with the combination. No infusion-related reactions, dose limiting toxicities, suspected unexpected serious adverse reactions or high-grade treatment related adverse events (TRAEs) that resulted in treatment discontinuance was seen. 12 subjects experienced at least one TRAE, and in all but one subject, these were low grade. One subject experienced a treatment-related immune system disorder. serious adverse events, all unrelated to treatment. TREM2 expression in archival tumor ranged from 0.0-20%. PY314 pharmacokinetics were linear, dose proportional, unaffected by concomitant pembrolizumab and with a half-life of 8-9 days. Best radiographic response was stable disease seen in 11 subjects (39.3%) ranging in duration from 9-42 weeks. 6 subjects with stable disease have progressed and 5 remain on treatment. Conclusions: PY314 was well tolerated and has an excellent safety profile both as a single agent and in combination with pembrolizumab. A recommended dose for expansion was derived and enrollment in five prespecified cancers is ongoing. Clinical trial information: 04691375.
IBI110 (anti-LAG-3 mAb) as a single agent or in combination with sintilimab (anti-PD-1 mAb) in patients with advanced solid tumors: Updated results from the phase Ia/Ib dose-escalation study.
Authors: Xu Nong , Mao Chenyu , Qian Jiong , Zheng Yulong , Jiang Haiping , Gao Yuan , Xiao Cheng , Xiong Anwen , Li Wei , He Yayi , Ren Shengxiang , Wang Lei , Yu Jia , Zhu Jun , Liu Ying , Zhou Caicun 
Published: June 2022

2650 Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. A phase Ia/Ib dose-escalation study evaluated IBI110 ± sintilimab in patient with advanced solid tumors; initial efficacy and safety data were previously presented (C Zhou et al. ASCO 2021; NCT04085185). Here, we reported the updated results. Methods: Eligible patients were ECOG PS 0-1 and had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Patients received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5/8/10 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from monotherapy to combination therapy was allowed at progression. The primary objectives were safety, tolerability, and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 28 patients (median age of 60.5 years [range 35-72], ECOG PS of 0 [n = 14] and 1 [n = 14]) were enrolled. Dose escalation was completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The safety profile was generally consistent with the initial. By investigator-assessment, best response was 1 confirmed partial response (PR) and 6 stable diseases (SD) with monotherapy. After crossing to combination therapy at progression, 8 patients who failed prior anti-PD-(L)1 mAb therapy achieved SD. Phase Ib: Overall, 45 patients (median age: 60.0 yr [range 33-74]; ECOG PS: 0 [n = 14], 1 [n = 31]) were enrolled in all dose levels. Dose escalation was completed and no DLT was observed. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (28.9%), anaemia (24.4%), and alanine aminotransferase increased (22.2%). TRAEs ≥ grade 3 occurred in 10 (22.2%) patients. Immune-related AE (irAE) incidence was 31.1%, and the most common irAE was hypothyroidism (15.6%). In 43 patients who had undergone at least 1 post-baseline tumor assessment, the investigator-assessed best response included 6 PRs (1 endometrial cancer, 4 NSCLC, and 1 SCLC patients) and 23 SDs. Three patients showed a progression-free survival > 1 year and continued treatment. Conclusions: IBI110 alone or plus sintilimab demonstrated acceptable safety profile and promising antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04085185.
Immune-related adverse events and immunotherapy efficacy in patients with cancer: A retrospective study.
Authors: Prather Lyndsey L , Ali Atif , Wang Hannah , Du Wendy , Chen Nan , Sheth Aakash , Sandulache Vlad , Sabichi Anita Lyn , Kemnade Jan Ole , Wang Daniel Ying 
Published: June 2022

2654 Background: Immune checkpoint inhibitors are revolutionizing cancer care and providing new treatment options with promising outcomes for many cancers. However, immune-related adverse events (irAEs) are not infrequent and can be severe. An intriguing relationship between the presence of irAEs and treatment efficacy has been described but lacks thorough characterization. We aimed to further elucidate a relationship between immune checkpoint inhibitor (ICI) irAEs and efficacy. Methods: We identified cancer patients treated with ICI from 2015-2021 across two institutions: Michael E DeBakey Veterans Affairs Medical Center (MEDVAMC) and Baylor St. Luke’s Medical Center (BSLMC). Clinical data including cancer type, irAEs type and grade, ICI response, progression free survival (PFS) and overall survival (OS) was collected. Using the Kaplan Meier method, survival curves were generated and comparisons were made amongst groups using the log-rank test. Fisher’s exact test was used to compare progression of disease between groups. To determine if variables were associated with survival, multivariable Cox regression analysis was used. Results: Of the 456 patients treated with ICI, irAEs were seen in 165 (36%) patients. Of these, 81 (49%) patients had grade 1 toxicities, most commonly arthritis, diarrhea, and dermatitis. 47 (28%) patients had grade 2 toxicities (colitis, hypothyroidism, adrenal insufficiency). 34 (21%) patients had grade 3 toxicities (pneumonitis, pancreatitis, hepatitis). 3 patients had grade 4 toxicities (pneumonitis, DRESS syndrome, and hepatorenal syndrome). 1 patient expired and 24 (15%) patients discontinued ICI due to irAEs. 55 (33%) of patients with irAEs were treated with steroids. For patients assessed for efficacy, objective response rate (ORR) to ICI was higher in patients with irAEs [47% (12% CR) vs 33% (11% CR)]. In fact, the presence of any irAEs was significantly likely to predict response to ICI (OR 1.90, 95% CI 1.25 - 2.86, p = 0.0026). In a subset of patients evaluable for survival (n = 375), patients with any irAEs had a significantly improved median PFS compared to those without irAEs (9.0 vs. 4.8 months, p = 0.0018). Multivariable analysis demonstrated that the development of any irAEs was related to a significantly improved OS (HR 0.63, 95% CI 0.43-0.89, p = 0.01). Conclusions: The development of irAEs in cancer patients treated with immunotherapy may predict better treatment efficacy and overall survival. Further prospective studies are needed to confirm these associations and mechanism of action.
Increased incidence of immune-mediated myocarditis in advanced skin malignancies treated with immune checkpoint inhibitors in the COVID-19 era.
Authors: Gradone Allison , Ma Vincent T , Fecher Leslie Anne , Yentz Sarah Elizabeth , Vasbinder Alexi , Hayek Salim S. , Lao Christopher D. 
Published: June 2022

2664 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced stage skin malignancies. Immunotherapy related adverse events (irAE) are toxicities associated with ICI therapy. Myocarditis is a rare life-threatening irAE. We attempt to characterize cases of myocarditis related to ICI therapy that have occurred since the start of the COVID-19 pandemic. Methods: We performed a single-center, retrospective cohort analysis of patients with advanced stage skin cancers who were treated with ICIs and identified cases of ICI-mediated myocarditis. ICI-mediated myocarditis was defined as evidence of myocardial injury in the setting of irAEs and exclusion of cardiovascular causes. Clinicopathologic variables and clinical outcomes were assessed in these patients. Results:A review of 361 patients that received ICI from 9/2014 – 10/2019 found 0 cases of ICI-mediated myocarditis. From 11/2019 – 12/2021, an additional 425 patients were identified of whom 11 (2.6%) developed ICI-mediated myocarditis. 10 patients had melanoma and 1 patient had Merkel cell carcinoma. 10/11 patients were male. 9/11 were treated with anti-PD-1 monotherapy and 2/11 were treated with ipilimumab with nivolumab. All patients had elevated high sensitivity troponin (median 361 pg/mL on presentation, reference range 0-19 pg/mL). 11/11 patients presented with elevated CPK (median 1734 IU/L, reference range 38-240 IU/L) and 8/11 presented with elevated AST:ALT ratio (median 1.58:1) on routine screening which prompted further investigation. 1 patient tested positive for COVID-19 13 days after initial biochemical concern for myocarditis, and 5 patients had received COVID-19 vaccines between 2.5-11 months prior to myocarditis onset. All patients were treated with high dose steroids, and 4 were treated with abatacept. 2 patients died within 30 days after diagnosis of myocarditis and 2 patients later died from malignancy progression. 2 patients developed progressive disease and 1 was successfully rechallenged with ICI with no myocarditis recurrence. 2 patients remain on active surveillance, 2 continue on a steroid taper, and 1 was lost to follow up. All patients with at least 5 months of follow up from myocarditis onset (n = 5) had persistently elevated HS-troponin despite normalization of CPK levels. Conclusions: In this single center study, we noted an increase in the frequency of ICI-mediated myocarditis in patients with advanced skin cancers during the pandemic era (2.6% vs 0% pre-pandemic) which is higher than reported in the literature (0.04-1.14%). The impact of COVID-19 during this time is suspicious and warrants further investigation. Therefore, we suggest heightened awareness in the COVID-19 era that elevated CPK levels and AST:ALT ratios merits further diagnostic investigation of ICI-mediated myocarditis.
TLD-1, a novel liposomal doxorubicin, in patients (pts) with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).
Authors: Hess Dagmar , Colombo Ilaria , Haefliger Simon , Rabaglio Manuela , Bastian Sara , Schwitter Michael , Eckhardt Katrin , Garzon Jesus Glaus , Hayoz Stefanie , Kopp Christoph , Holer Lisa , Mc Laughlin Anna , Kloft Charlotte , Sessa Cristiana , Stathis Anastasios , Halbherr Stefan , Baumgartner Christian , Joerger Markus 
Published: June 2022

3027 Background: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional liposomal formulations of doxorubicin in preclinical in vivo mouse breast cancer models. This phase I first-in-human trial is aiming to determine the recommended phase II dose (RP2D), toxicity profile, pharmacokinetics and preliminary activity. Methods: Patients with a maximum of 3 prior lines of systemic chemotherapy and preferably anthracycline-sensitive disease were eligible. TLD-1 was administered on day 1 iv over 60-90 minutes (depending on individual dose) q 21 days, for up to 6 or 9 cycles (according to prior anthracycline-exposure) with premedication of 8mg dexamethasone. Dose escalation with dose levels (DL) 1-7 of 10, 16, 23, 30, 35, 40 and 45mg/m2 started with an accelerated titration design, treating one pt at each DL up to DL6 (40mg/m2) followed by a modified continual reassessment method at DL7 due to observed toxicity. Results: 30 pts (F:M = 24:6) have been treated, one each at DLs 1-6, 15 pts at DL7 and an additional 9 pts at DL6. Most frequent tumor types included breast (n = 13), ovarian (n = 6), cervical cancer (n = 2) and cholangiocarcinoma (n = 2). Median age was 67.5 years (range:38-83), 13 pts were exposed to prior anthracyclines. The median number of cycles was 4 (range:1-9). No dose-limiting toxicities (DLT) occurred during cycle 1. At DLs 1 to 5, no treatment-related G3 AEs (TRAE) were observed. At DL6, there was one case of mucositis G3, one of palmar-plantar-erythrodysesthesia (PPE) G3 and one of anemia and neutropenia G3 each. One patient with pre-existing valvular cardiopathy developed symptoms of heart-failure G3 after 8 cycles. Echocardiography showed severe mitral regurgitation with normal LV-EF. In addition one case of urinary-tract infection G3 was seen. Dose-modifications or -delays due to AEs occurred in 7/50 cycles. At DL7, one case of mucositis G3, 3 events of PPE G3 and one case of fatigue G3 were reported. In addition, one case of infection with shingles occurred. Dose-modifications or -delays due to AEs occurred in 12/61 cycles. Shingles and heart failure were reported as SAEs. All toxicities listed above were categorized as TRAE. 29/30 pts were evaluable for response. Three breast cancer pts had a partial response, 2 at DL7 and 1 at DL6, 14 pts had stable disease. Conclusions: No DLT was observed up to DL7. RP2D was defined at 40mg/m2 due to cumulative PPE G3 at DL7. The trial is ongoing with a comparative PK-part evaluating the two iv liposomal formulations of doxorubicin TLD-1 and Caelyx. Clinical trial information: NCT03387917.
An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection.
Authors: Shao Yang , Bao Hua , Wang Zheng , Ma Xiaoji , Guo Wei , Zhang Xiangyu , Wang Xinyu , Chen Yikuan , Mo Shaobo , Liang Naixin , Ma Qianli , Li Yaqi , Zhang Long , Tan Fengwei , Xue Qi , Liu Fangqi , Cai Sanjun , Gao Shugeng , Peng Junjie , Zhou Jian 
Published: June 2022

3037 Background: Although most cancer can benefit from early detection by more effective treatments and better prognosis, current screening programs are only limited to tumor-specific tests for a subset of common cancers. To benefit a broader population and outweigh the risks of single-cancer tests, an effective and affordable multi-cancer test should be developed for sensitive early detection of multiple cancers and accurate prediction of cancer tissue of origin simultaneously. Methods: In this study, we enrolled 971 cancer patients of the most prevalent and lethal cancer types, including primary liver cancer (PLC, N= 381), colorectal adenocarcinoma (CRC, N= 298), and lung adenocarcinoma (LUAD, N= 292), as well as 243 healthy controls. The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio. Five fragmentomic features representing cfDNA fragmentation size, motif sequence, and copy number variation were extracted from processed whole-genome sequencing (WGS) data of the participants to build the base models. Each base model implemented five machine learning algorithms for model training, and the optimal base models were used to create the final multi-dimensional model through ensemble stacked machine learning. The integrated multi-cancer model is composed of the first-level binary cancer detection model and the second-level multi-classification cancer origin model. The training cohort was used to train the models with 10-fold cross-validation. The test cohort remained untouched during model construction and was solely used for performance evaluation. Results: Our cancer samples are highlighted by mostly early-stage diseases (early-stage PLC: 88.5%; CRC: 100.0%; LUAD: 100.0%). The cancer detection model reached an area under the curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals in the test cohort. At 95.0% specificity, the sensitivity of detecting all cancer is 95.5%, and 100.0%, 94.6%, and 90.4% for PLC, CRC, and LUAD, respectively. Its sensitivity is consistently high for early-stage, small-size tumors. The cancer origin model demonstrated an overall 93.1% accuracy for predicting tissue of origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Furthermore, the model's cancer detection and origin classification performance remained robust when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). Conclusions: We utilized multiple plasma cfDNA fragmentomic features to build an ensemble stacked machine learning model. The assay reached ultrasensitivity and accuracy for multi-cancer early detection, shedding light on leveraging cfDNA fragmentomics for early screening in clinical practice.