bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib study of olinvacimab (O) with pembrolizumab (P) in patients with recurrent glioblastoma (rGBM).
Authors: Nowak Anna K. , Cher Lawrence , Bowyer Samantha , Gan Hui Kong , Long Anne Poh , Balasubramanian Adithya , Lee Seon Young , Lee Weon Sup , Yoo Jin-San 
Published: May 2020

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose level 1) or O 16mg/kg day 1/8/15 q21d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Pts were reviewed weekly and underwent DCE-MRI at baseline and 6-weekly. Treatment continued to progression, toxicity or withdrawal. Results: 9 pts, median age 53 (range 34-67) were recruited and received at least one study treatment. Median time since diagnosis was 15.6 months. 7 (78%) had KPS 90 and 2 (22%) KPS 80. 3 pts received O 12mg/kg with P, completing a median 3 cycles (range 2-6). As no Dose Limiting Toxicities (DLTs) were seen, 3 pts were treated with O 16mg/kg with expansion total 6 when no DLTs were observed. At 16mg/kg, a median of 2 treatment cycles was received (range 2-6). Treatment was ceased due to progressive disease (PD) in 8 pts with one ongoing at data cutoff. No DLTs were observed in any pts. Three grade 3 treatment emergent adverse events (TEAEs) were noted (blurred vision, fatigue, and seizure). Hemangioma is a known toxicity of O and was seen in 6 pts, with 11 grade 1 and 1 grade 2 event. 4 pts (44%) had stable disease (SD) and 5 pts (56%) had PD as best response. Conclusions: The combination of O with P was safe and tolerable at the full single agent dose of each drug. No DLTs were observed. The combination did not show efficacy in this setting. Clinical trial information: NCT03722342.
Identification of genetic alterations in childhood and adolescence glioblastoma (GBM) using next generation sequencing strategy.
Authors: Corrêa Debora Cabral de Carvalho , Dias-Oliveira Indhira , Alves Maria Teresa de Seixas , Saba-Silva Nasjla , Capellano Andrea Maria , Dastoli Patrícia , Cavalheiro Sérgio , Petrilli Antonio Sergio , de Toledo Silvia Regina Caminada 
Published: May 2020

e14547 Background: Glioblastoma (GBM) is the most aggressive brain malignancy with a heterogeneity molecular profile and accounts for no more than 3-5% of Central Nervous System tumors in children. Despite its rarity, pediatric GBM pertain different molecular genetics, outcome and effectiveness to therapies and remains an equally lethal tumor in children. Identification of genetic alterations in GBM of childhood and adolescence is important to refine molecular classification, define prognosis and therapeutic strategies. We aimed to detect and investigate molecular changes with potential prognostic marker and therapeutic target in GBM, using next generation sequencing (NGS) strategy. Methods: We selected 41 GBM samples from patients treated at Pediatric Oncology Institute/GRAACC. NGS was performed to identified genetic alterations in tumor samples using Oncomine Childhood Cancer Research Assay (OCCRA) panel, specific genetic panel for childhood and adolescence neoplasms. Results: We selected 41 GBM samples and identified 33 mutated genes. The most commonly detected genetic alterations were involving TP53, PDGFRA, PIK3CA, NF1, MYC, MET and genes with histone-related functions, including H3F3A and ATRX. Mutations in H3F3A K28M, ATRX and TP53 were most recurrent. ATRX alterations, either nonsense substitution or frameshift deletion, were exclusively found in patients with H3F3A K28M mutations. TP53 loss-of-function was exclusive in 9 of 41 (22%) tumors. In 7 of 9 cases (78%) harboring both H3F3A and TP53 mutations, patients died due to disease progression . In these patients, H3F3A-TP53 mutation is suggested to be unfavorable prognostic factor. Copy number alterations were found in 30% of GBM cases and PDGFRA-amplifications were the most frequent. PDGFRA-amplification was exclusively found in patients with H3F3A K28M mutations and 75% of these patients did not survived longer than two years. Conclusions: Molecular profiling based on NGS genetic panel, specific for pediatric tumors, can provide information about potential prognostic biomarkers for GBM of childhood and adolescence. Thus, wider understanding about GBM biologic heterogeneity may lead to personalized therapeutic strategies for pediatric patients.
The correlation between molecular characteristics and treatment outcomes in patients (pts) with grade 2-3 (G2-3) gliomas.
Authors: Fallah Jaleh , Tatineni Vineeth , Tom Martin C. , Wei Wei , Park Deborah , Tewari Surabhi , Stevens Glen , Chao Samuel T. , Suh John H. , Peereboom David M. , Murphy Erin Sennett , Ahluwalia Manmeet Singh 
Published: May 2020

e14551 Background: In a retrospective study, we investigated the correlation between the molecular characteristics and treatment outcomes in pts with G2-3 glioma. Methods: Pts with G2-3 glioma and known IDH mutation status who were diagnosed between 1994 and 2017 were analyzed. In most of the pts, IDH mutation was determined by immunohistochemistry only. Overall survival (OS) was defined as the date of biopsy/surgical resection to the date of last follow up or death. OS was estimated by Kaplan-Meier method and compared by log rank test. Results: 606 pts with G2 (81%) or G3 (19%) glioma were included. The median age at diagnosis was 38 years (Interquartile range 27-52), 55% of the pts were male, 83% were white, 47% had IDH-mt tumor and 67% underwent surgical resection. The median follow-up was 55.6 months (mo). The median OS (mOS) in pts with IDH mutated (mt) and IDH wild type (wt) tumor were 201 and 128 mo, respectively. The predictors of worse OS in pts with IDH-mt tumor included G3, receipt of chemotherapy or radiation therapy (RT), bilateral disease and lack of 1p/19q codeletion. The determinants of worse OS in pts with IDH-wt tumor included male gender, receipt of chemotherapy or RT, history of prior malignancy, smoking, G3, astrocytoma histology, no surgical resection, EGFR amplification, and lack of 1p/19q codeletion. The mOS by IDH, 1p/19q, and MGMT status is summarized in the table. RT and chemotherapy were more commonly used among pts who had G3 glioma and those who underwent biopsy only. Conclusions: Tumor grade continues to be a determinant of pt outcomes in the setting of molecularly defined gliomas. Presence of 1p/19q codeletion is a predictor of favorable OS in pts with G2-3 glioma. Surgical resection is a determinant of OS in pts with IDH-wt G2-3 gliomas, but not in pts with IDH-mt tumor. The worse OS in pts who were treated with RT or chemotherapy is likely due to the use of these treatment modalities in more aggressive tumors and in those who only had biopsy. [Table: see text]
Risk of bleeding and significant thrombocytopenia in cancer patients treated with immune checkpoint inhibitors.
Authors: Kewan Tariq Zuheir , Ahmed Ramsha , Alqaisi Sura , Covut Fahrettin , Flores Monica , Babar Arslan , Haddad Abdo S. , Daw Hamed 
Published: May 2020

e15000 Background: Immune checkpoints inhibitors (ICIs) are associated with multiple side effects. Complications can affect any organ system including; endocrine, gastrointestinal, pulmonary, and less frequently hematological system.We evaluated the risk of bleeding and significant thrombocytopenia in cancer patients (pts) treated with ICIs. Methods: Cancer pts treated with ICIs between 01/2015 and 7/2019 at Cleveland Clinic Foundation were retrospectively reviewed. Platelets (plts) count and hemoglobin (hb) level at baseline, after one month and 3 months of treatment were reviewed. Thrombocytopenia was defined as plts count < 150,000. In pts with thrombocytopenia at baseline, more than 50% drop in the plts count was considered significant. Pts were followed-up for one year after ICIs treatment initiation for significant bleeding. Results: We identified 555 cancer pts treated with ICIs. Of these pts 65% were males. Among all included pts, 53% had lung cancer, 23% had genitourinary cancers, 17% had melanoma, 3% had gastrointestinal cancers, and 5% had other cancer types. Nivolumab, pembrolizumab, ipilimumab, and atezolizumab were used in 62%, 27%, 14%, and 12% respectively. Clinically significant bleeding, thrombocytopenia after one month and 3 months of treatment were identified in 21%, 6%, and 7% respectively. Of all pts who developed bleeding, 8% had gastrointestinal bleeding, 5% had intracerebral hemorrhage, and 3 % had hemoptysis. Only 23% of the pts who developed bleeding were receiving anticoagulation therapy. In multivariate analysis, breast cancer as primary malignancy (p = .03) and atezolizumab (p = 0.02) were predictors of clinically significant bleeding. Also, nivolumab was associated with increased risk of significant thrombocytopenia after one month of treatment (p = .02). There was no significant association between the use of specific medication and the development of significant anemia. Median overall survival time was not statistically different in patients who had bleeding compared to no bleeding group, 12.6 months (95% CI:10.8-14.5) and 12.4 months (95% CI:10.3-15) respectively (p = .21). Conclusions: In this cohort study, atezolizumab and breast cancer were significantly associated with increased risk of bleeding. The use of nivolumab was associated with a greater risk of thrombocytopenia after one month of treatment. Prospective studies are needed for better understanding of the hematological side effects of ICIs.
Correlation of clinical activity of NEO201 mAb with the expression of NK activation markers and levels of soluble factors.
Authors: Morelli M. Pia , Fantini Massimo , Houston Nicole D. , Lee Jung-min , Zimmer Alexandra Dos Santos , Lipkowitz Stanley , Trewhitt Kathryn , Arlen Philip M. , Tsang Kwong Y. , Annunziata Christina M. 
Published: May 2020

e15002 Background: NEO-201 is a humanized IgG1 mAb that targets tumor-associated variants of CEACAM-5/6. NEO201 exerts anti-tumor activity by (NK)-mediated ADCC, CDC, and by enhancing NK cell cytotoxicity through blockade of CEACAM5-CEACAM1 interaction. The first in human phase I clinical trial is ongoing. Neutropenia caused DLT and was observed at 2mg/kg (DL 2). At DL2, 2/6 patients with colorectal cancers had stable disease. In the present study we evaluated the correlation between response, NK status, and profiles of soluble factors. Methods: This is a classic 3+3 dose escalation. NEO-201 is administered intravenously every 2 weeks, with 4 dose levels planned (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). So far, 3 patients received DL1 and 6 patients DL2. Safety is evaluated according to CTCAEv5.0, and response according to RECISTv1.1. Biological samples are collected at baseline, at 4, 24 and 72 hours after the first dose, and before C1D15 dose to understand NEO-201 pharmacokinetics (PK), effects on immune profile and correlation with treatment toxicity and response. CD56+/CD16+ NK cells were evaluated for modulation of NKG2D, CD107a, NKp46 (activation markers), and CEACAM1 (inhibitory marker) by flow cytometry. Soluble factors (cytokines, sMICA and sCEACAM5) were evaluated by ELISA. Results: Among the 3 patients achieving radiological SD, one (DL1) had clinical progression (PD) without radiological progression after 2 cycles due to mucous producing disease, a second patient (DL2) went off study after 2 cycles for drug unrelated issues, and the third patient (DL2) has stable disease (SD) for 6 months without significant toxicity. All other patients had radiologic PD after 2 cycles. Interestingly, baseline CD56+/CD16+ NK cells from the two patients with SD showed an increase in NKG2D, CD107a and NKp46, and a low expression of CEACAM1. They also had low serum levels of sMICA, sCEACAM5 and IL-6. On contrary, CD56+/CD16+ NK cells from patients with PD had low expression of NKG2D and CD107a, high expression of CEACAM1, and high levels of sMICA. Conclusions: High expression of activating markers and low expression of CEACAM1 on CD56+/CD16+ NK cells, as well as low levels of sMICA and sCEACAM5 correlate with clinical response to NEO-201. Thus, the activity of NK cells may serve as predictors for efficacy of tumor-targeting antibody therapy. Further correlation of these biomarkers with PK and CEACAM1/5/6 expression in patients’ tissue samples will provide further support for optimizing the use of NEO201. Clinical trial information: NCT03476681 .
MSB2311, an anti-programmed death-ligand 1 antibody, in advanced solid tumors and hematological malignancies: Safety and tolerability, early anti-cancer activities from a phase I study in Chinese patients.
Authors: Hu Xichun , Gong Jifang , Ji Dongmei , Shen Lin , Li Yufeng , Wang Mengde , Huang Yingjie , Xia Zhenzhong , Lu Lingmin , Huang John , Xu Li , Li Jenny , Wan Yuntao , Qian Xueming 
Published: May 2020

e15011 Background: MSB2311 is a novel humanized programmed death-ligand 1 (PD-L1) antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. Methods: Patients with metastatic solid tumors and selected hematological malignancies progressed after standard treatments were enrolled in this Phase I study. In dose escalation part, MSB2311 was given at levels of 3, 10, and 20 mg/kg intravenously every 3 weeks. At the dose expansion part, patients with enriched biomarker expression, either EBV positive, PD-L1 positive, MSI-High or TMB-High, were enrolled and dosed either in 20mg/kg Q3W or 10mg/kg Q2W. Primary objectives are to evaluate the safety and tolerability and to identify MTD/MAD and RP2D. Secondary objectives include the assessment of pharmacokinetics, immunogenicity, and preliminary efficacy per RECIST1.1. Results: At data cut-off at Jan 19, 2020, 27 Chinese patients have been treated, 18 (66.7%) of them received at least 4 cycles of MSB2311. No dose limiting toxicity was reported and MTD has not been identified. The most common treatment-emergent adverse events (TEAEs) ( > 10%) included: anemia, hypothyroidism, hyperglycemia, hypertriglyceridemia, nausea, vomiting, fatigue, malaise, pyrexia and cough. Eleven patients (40.7%) experienced Grade 3 TEAEs, and 6 patients (22.2%) experienced SAEs. One lymphoma patient experienced grade 4 hypercalcemia and platelet count decreased, which were assessed as related to study drug by the investigator. MSB2311 displayed a linear pharmacokinetic profile with calculated T1/2 of about 10-13 days. Among 18 evaluable patients treated with 20 mg/kg Q3W, the best response of PR was observed in 4 out of 12 patients with solid tumors including NSCLC, NPC and Gastric cancer, and 1 out of 6 patients with lymphoma. The mean duration of response was 127 (range 38-278) days. Conclusions: MSB2311 demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors and hematological malignancies.
Prospective analysis of antinuclear antibodies prevalence in a pan-tumor sample.
Authors: Roa Silvia , López-Alfonso Ana , Toboso del Amo Inmaculada , Falagan Sandra , Zambrana Francisco , Lopez-Gomez Miriam , Jimenez-Gordo Ana M. , Gomez Raposo Cesar , Merino Maria , Aguayo Cristina , Casado Enrique , Moreno-Rubio Juan , Sereno Maria 
Published: May 2020

e15012 Background: Antinuclear antibodies (ANAs) constitute a spectrum of autoantibodies targeted to nuclear and cytoplasmic components of the cells considered serological markers for different autoimmune disease. However, ANAs are also presented in different types of cancers. Here, we present an exploratory analysis of ANAs patterns detected in patients with a recent cancer diagnosis. Methods: We carried out a prospective analysis of patients recently diagnosed of cancer in two centers. All were tested for ANAs from January to December 2019. Clinical-pathological features were collected from clinical reports. Results: 190 patients were included with different tumors: Lung(56.3%); colon/rectum(16.3%); head-neck(10.5%); pancreas(3.6%); stomach(3.1%); sarcoma(3.1%); urothelial(2.6%) and others( 3.6%). Most of the patients (pts) had stage IV (65.7%) and III (26.8%). Several histologies were included: adenocarcinoma(55.7%); squamous (32.6%) and others (transitional, clear cells, small cell and mesotelial/sarcoma). Chemotherapy was the main treatment (73.6%pts) followed by immunotherapy (11.5%pts), targeted therapy (6.8%pts) and chemo-inmunotherapy (3.1%pts). Among all pts included, only 13 had autoimmune disease: polymyalgia rheumatica (1pt); psoriasis (4pts), bronchial hyperreactivity (2pts) and hypotiroidism (6pts). In this cohort, we found that 60/190, 31.5%pts, showed positive ANAs (+) titers by immunofluorescence analysis. Different patterns were described according to First International Consensus on Standardized Nomenclature of ANAs. The predominant was a speckled pattern presented in 26% pts; secondly, a nucleolar pattern in 16.6% pts and CENP-F AC14 was presented in 8.3%pts. More minoritary patterns were also described. Patients with advanced lung cancer included 56.6% of ANAs (+) cases followed by colorectal cancer (11.6%). Adenocarcinoma (73,3 % pts) and squamous carcinoma (16,6% pts) were the most common histologies among ANAs (+) cases but none of the small cell carcinoma were ANA(+). The majority of ANAs (+) patients were on chemotherapy (73.3 % pts) followed by immunotherapy (16.6% pts). On the other hand, 4/13 of patients with autoimmune diseases presented ANAs(+) titers (CENT-F, scl70 and AC3 patterns). The only patient who developed a severe inmune-related toxicity was ANA negative. Conclusions: In this study, we describe the prevalence of ANAs and their patterns in a cohort of cancer patients. A complementary description of relevant clinical-pathological features in ANAs(+) subgroup is also reported.
A pilot trial of multiple-TSA-specific adoptive immune cell (MAIC) as adjuvant therapy in gastrointestinal cancer.
Authors: Shi Wei , Song Jin , Cui Xiaohong , Wang Yan , Mei Boyuan , Ren Shucheng , Wang Haiwen , Chen Huan , Li Li , Zhang Henghui , Zhang Hao , Lu Jilin 
Published: May 2020

e15013 Background: Given the heterogeneity of tumors, more tumor antigens need to be covered for better efficacy in oncologic immunotherapy. We conducted a pilot clinical trial to evaluate the safety and efficacy of adoptive immune cell therapy targeting multiple tumor specific antigens in individual patients. Methods: A total of 10 patients bearing resectable gastrointestinal tumor are going to be recruited in the study. The tumor-specific antigens of each patient were identified by RNA sequencing of the surgical tumor tissue. And then the antigenic peptides were synthesized and adapted to produce the multiple-TSA-specific adoptive immune cells (MAIC), including dendritic cell (DC) and cytotoxic T lymphocyte (CTL). 1st dose of MAICs injected during the 2nd or 3rd week after surgery; three doses of MAICs administered at 3-week intervals. Results: Currently, 4 patients have been enrolled, as shown in Table. The first enrolled patient, P01, underwent adjuvant MAIC therapy and have no progression nearly 9 months. P02, P03 and P04 developed new lesions about 3 months after the 1st surgery. After the 2nd surgery, tumor antigens were modified and MAIC targeting new antigens were given for adjuvant therapy. Up to now, there were no death events with survival months from 6.57 to 9.10. Safety evaluation showed that no irAE occurred in 4 patients. Intriguingly, antigenic drift was observed in patient P02.The top 3 antigens were shift from GPC3, AFP and GAGE10 to MAGEA1, GPC3 and CTAG2. And the mutation profile of tumors revealed totally different tumor clones with no shared SNV mutation between two surgery lesions at all. Through TCR sequencing, we found new T cell clones introduced by MAICs persisted in peripheral blood (sum ratio variated from 6.47% to 9.68%). Among them, specific T cell clones were identified targeting four antigens, including GPC3, AFP, TERT and MAGEA1. Among them, TERT-specific T cell clones shew highest expansion ratio, from 0.63±0.17% in PBMC to 7.85±3.10% in CTL. Conclusions: Treatment with MAICs have be proved safety in resectable gastrointestinal cancer. And all together four-antigen-specific T cell clones elevated apparently in peripheral blood after the 1st infusion of MAIC, reflecting the advantage of MAIC at renewable antigenic targets. [Table: see text]
Immunotherapy combining NK and T cell activation with IL-15 super agonist (N-803), off-the-shelf high-affinity CD16 NK (haNK) or PDL1 targeted haNK and checkpoint inhibitor in relapsed/refractory advanced pancreatic cancer.
Authors: Seery Tara Elisabeth , Kistler Mira , Nangia Chaitali Singh , To Christina Ann , Reddy Sandeep K. , Sender Leonard S. , Lee John H. , Soon-Shiong Patrick 
Published: May 2020

e15015 Background: Pancreatic cancer is the third leading cause of cancer-related deaths in the US. Patients who relapse after first/second-line chemotherapy have a 2 month median survival. In this relapsed population, there is no approved therapy. Effective response requires a coordinated approach that orchestrates both the innate and adaptive immune system. We hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with clinical benefit. We describe a first-in-human novel combination immunotherapy protocol of chemoradiation, cytokine-induced NK and T cell activation, checkpoint inhibition, and off-the-shelf allogeneic high-affinity NK cell infusion (haNK). We report the first complete response (CR) to an NK-based immunotherapy combination in pancreatic cancer. Methods: QUILT-3.039/3.060/3.070/3.080 enrolled a total of 12 patients (8M/4F), median age 57.5 (35-74), ECOG 0-2) with advanced pancreatic with progressive disease after prior chemotherapy. There were differences in the dose and schedule of agents used across the various protocols. Common elements were: 1. Reduced dose metronomic chemotherapy (combinations of aldoxorubicin, gemcitabine, abraxane, oxaliplatin, 5FU, and cyclophosphamide) 2. SBRT, 3. Avelumab, 4. N803 (IgG1 Fc-engineered IL-15-fusion protein), 5. Allogeneic haNK cells. This experience led to a SPIND substituting allogeneic haNK cells with allogeneic haNK cells targeted against PDL-1. All treatment was in an outpatient setting. A median of 6 cycles of haNK cells (2-15) were delivered for a cumulative median dose of 29.0 x 109 cells per patient (8.0-56.0 x 109). Results: In 12 patients across 4 studies, a median of 6 (2,15) cycles of treatment were delivered, resulting in median PFS of 6.6 mo (3.3-12.4), OS 8.1 mo (5.0-27.0). 11/12 (92%) patients experienced stable disease (SD) for > 8 weeks. 11/12 (92%) also experience at least 1 grade 3 AE: neutropenia (92%), anemia (50%), febrile neutropenia (17%), diarrhea (8%), hyperglycemia (25%), hyponatremia (17%), and elevated alkaline phosphatase (8%). The SPIND patient (79 yo M, ECOG 1) received 7 cycles and achieved a CR by PET with 5 months follow-up to date. No grade 4 AEs were seen. No severe immune related AE’s were seen. Conclusions: Orchestrated immunomodulatory outpatient combination treatment is feasible and results in clinical benefit and CR in selected patients with acceptable toxicity.