bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive evaluation of quantitative spatial profiling of the tumor microenvironment by multiplex immunofluorescence in recurrent glioblastoma treated with PD-1 inhibitors.
Authors: Cieremans David , Kim Ju Young , Valencia Ariana , Santos Justin , Bordeaux Jennifer , Tran Thai , Vaupel Christine , Dakappagari Naveen , Tangri Shabnam , Iwamoto Fabio Massaiti
Published: May 2020

e14524

Background: PD-1 inhibitors have shown limited efficacy in glioblastoma (GBM) due to microenvironment immunosuppression and low tumor mutational burden. In GBM, PD-L1 expression is not a predictive marker for response to PD-1 or PD-L1 inhibitors. Multiplex immunostaining panel technology allows for detailed analyses of tumor microenvironment cells and their interaction. Methods: Pre-treatment tumor tissue was collected retrospectively from 27 patients in our neurooncology database at Columbia University Irving Medical Center with primary glioblastoma who were diagnosed within the past three years, had surgery here, and were either treated with SOC therapy (n = 8) or PD-1 inhibitors at recurrence (n = 19). Multiplex immunofluorescence was done for 1) CD11b/IDO1/HLADR/GFAP, 2) PD1/PD-L1/GFAP, and 3) CD4/CD8/CD25/FoxP3/Ki67/GFAP. Results: Multiplex immunofluorescence panels did not show any correlation with outcomes in patients treated with SOC therapy (non-immunotherapy). Among the 19 patients treated with PD-1 inhibitors, those with more HLA-DR positive cells had worse outcomes (p = 0.02). PD-L1 expression on tumor cells was not predictive of outcomes. There was a correlation trend between PD-1/PD-L1 interaction score (p = 0.08), which measures density of PD-1-positive cells in proximity to PD-L1-positive cells, and outcomes. This assay allowed us to evaluate tumor-associated macrophages, myeloid-derived suppressor cells, CD8+ lymphocytes, and CD4+ T regulatory cells; however, none of these were predictive of survival. Conclusions: Quantitative spatial profiling by multiplex immunofluorescence is feasible in FFPE glioblastoma tissue. More refined and extensive quantitative and spatial microenvironment analyses may allow for the development of biomarkers for immunotherapy in GBM.
Effect of temozolomide chronotherapy in patients with high-grade glioma.
Authors: Atluri Himachandana , Campian Jian Li , Talcott Grayson , Meyer Melissa , Slat Emily , Rubin Joshua , Huang Jiayi , Chheda Milan G , Johanns Tanner Michael , Tao Yu , Govindan Ashwin
Published: May 2020

e14525

Background: High grade gliomas (HGG) (the most common being glioblastoma) are the most common primary CNS malignancy in adults. Mainstay of therapy is surgical resection followed by concurrent radiation and temozolomide (TMZ) followed by adjuvant TMZ. Unfortunately, prognosis remains poor and optimization of current therapy is critical. Chronotherapy is defined as improvement in treatment outcomes by maximizing treatment efficacy and minimizing toxicity by administering medications in accordance with biological rhythms of the patient. In a mouse model, there was greater anti-tumor efficacy during morning administration of TMZ. This trial was designed to determine the feasibility and potential clinical impact of chrono-therapeutically administering TMZ in patients with HGG. Methods: Adult patients ( > 18 years) with HGG (WHO Grade III/IV) were eligible. Patients were screened and consented prior to initiation of monthly TMZ therapy. Eligible patients were randomized to TMZ in the morning (AM) before 10AM or in the evening (PM) after 8PM. Pill diaries were recorded for drug administration time and compliance. Fact-Br Quality of Life (QoL) surveys were administered to patients at the time of enrollment in the trial and at the end of treatment to measure differences in QoL in both groups. Circadian rhythm was recorded by Actiwatch. Adverse events (AE), overall survival (OS) and progression free survival (PFS) were measured for each group. Results: At the time of submission, a total of 28 patients were evaluated. 15 patients were in AM group and 13 in PM group. It is feasible for participants to take TMZ per study assignment. There was no significant difference in the QoL based on the Fact-Br dataset in the four main categories of physical well-being, social/family well-being, functional well-being and emotional well-being. The Friedman’s two-way nonparametric ANOVA tests were used to analyze the differences across time points. Cytopenias are a known adverse effect of TMZ. There was a trend towards worsening lymphocyte counts in the AM group compared to PM group, although not statistically significant. There was no statistical significance in PFS or OS in patients with newly diagnosed glioblastoma. Conclusions: Chronotherapy with TMZ is feasible. A trend of worsening lymphocyte counts is noted in AM treatment group compared to PM group but was not statistically significant. No difference in OS or PFS was noted, although sample size was too small to effectively assess this. A larger study will need to be conducted to effectively assess the effect of chronotherapy on survival. Clinical trial information: NCT02781792.
Combined structural and perfusion MRI enhanced by machine learning may outperform standalone modalities and radiological expertise in high-grade glioma surveillance: A proof-of-concept study.
Authors: Roettger Diana , Siakallis Loizos , Sudre Carole , Panovska-Griffiths Jasmina , Mulholland Paul , Thorne Lewis , Shaikh Faiq , Bisdas Sotirios
Published: May 2020

e14528

Background: Treatment monitoring in patients with High-Grade Glioma (HGG) and identification of disease progression, remains a major challenge in clinical neurooncology. We aimed to develop a support vector machine (SVM) classifier utilising combined longitudinal conventional and Dynamic Susceptibility Contrast (DSC) perfusion MRI to classify between Stable Disease (SD), Pseudoprogression (PsP) and Progressive Disease (PD) in glioma patients under surveillance. Methods: Conventional (269) and perfusion (62) MRI studies of HGG patients acquired between 2012 and 2018 were prospectively analysed. Study participants were separated into two groups: Group I with a single DSC time point (64 participants) and Group II with multiple DSC time points (19 participants). The SVM classifier was trained using all available MRI for each group. Classification accuracy was assessed for the use of features extracted from different feature dataset and time point combinations and compared to the experienced radiologists’ predictions. Results: The study included 64 participants (mean age: 48.5 ± 12.8 yrs [standard deviation], 24 female). SVM classification based on combined perfusion and structural features outperformed standalone datasets across all groups. For the clinically relevant classification step (SD/PSP vs PD), both feature combination as well as the addition of multiple DSC time points, improved classification performance (lowest median error rate: 0.016). The SVM algorithm outperformed radiologists in predicting lesion destiny in both groups. Optimal performance was observed in Group II, in which SVM sensitivity/specificity/accuracy was 100/91.67/94.7% for analysis based on the first time point and 85.71/100/ 94.7% based on multiple time points compared to 60/78/68% and 70/90/84.2% for the respective radiologist classifications. In Group I, the SVM also exceeded radiologist predictions, albeit by a smaller margin and resulted in sensitivity/specificity of 86.49/75.00/81.53% (SVM) compared to 75.7/68.9/73.84% (radiologists). Conclusions: Our results indicate that the addition of multiple longitudinal perfusion time points as well as the combination of structural and perfusion features significantly enhance classification outcome in treatment monitoring of HGGs and machine-learning-assisted diagnosis has potentially superior accuracy than the radiologist's visual evaluation and expertise.
Survival in adult and pediatric patients with medulloblastoma: A 2018 SEER-based analysis.
Authors: Moisander-Joyce Hanna , Sinha Anoushka , Fernandez-Ledon Shannon , Lee Davon , Hatano Satoki , Kahn Justine , Garvin James , Zacharoulis Stergios , Gartrell-Corrado Robyn D
Published: May 2020

e14529

Background: Medulloblastoma (MB) is a malignant neuroectodermal tumor accounting for 30% of pediatric and only 1% of adult brain tumors. In previous studies comparing survival in pediatric and adult MB from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) database no difference has been found. However, diagnostic subgroup analyses have been limited. Methods: We examined survival in children (age 0-19) and adults (20-79) coded as MB in the 2018 SEER database (2000-2016). We used Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI). MB in SEER-18 is defined as ICD-O-3 histology codes 9470–9474 (n = 1,728). ICD 9473, supratentorial PNET (sPNET, n = 97) is biologically distinct and therefore it was analyzed separately. Results: We found that 5-year survival for MB, excluding sPNET, was similar in children (n = 1,091, 75.3%) and adults (n = 488, 79.1%) (HR = 0.97, CI: 0.79 – 1.17, p = 0.50). Furthermore, subtype analyses showed no survival difference comparing adults and children with desmoplastic nodular MB (n = 222, p = 0.09), large cell MB (n = 73, p = 0.46), or MB NOS (n = 1330, p = 0.10). Yet, children with sPNET had improved 5-year survival (n = 65, 72.3%) compared to adults (n = 29, 51.7%) (HR = 2.0, CI: 1.10 – 3.92; p = 0.02,). These findings indicate that while survival in patients with MB is similar across age groups, children with sPNET have improved outcomes. Conclusions: In summary, 2018 SEER data for MB continue to show no survival difference between adults and children, suggesting adult patients could appropriately be entered on pediatric MB treatment protocols. Further analyses of the 2018 data are ongoing adjusting for sex, race, and treatment (chemotherapy or radiation). For sPNET, the apparent improved outcomes for children merit further detailed investigation and will be re-evaluated using the new 2016 World Health Organization classification.
Craniospinal irradiation in patients diagnosed with glioblastoma with primitive neuronal component prevents distant intracranial and leptomeningeal recurrences.
Authors: Eastman Boryana M , Cimino Patrick J , McGranahan Tresa , Halasz Lia Moriguchi
Published: May 2020

e14540

Background: Glioblastoma (GBM) is the most common primary central nervous system (CNS) malignancy. In recent years, molecular and histological analyses have identified GBM with primitive neuronal component (GBM-PNC) as a distinct entity with poor regional control and worse overall prognosis. GBM-PNCs are more prone to CNS dissemination and leptomeningeal (LM) metastasis, occurring in up to 40% of patients. Given the concern for distal CNS spread, we hypothesized that craniospinal irradiation (CSI) may be an effective treatment option for GBM-PNC. Methods: We performed a retrospective chart review of patients diagnosed with GBM-PNC treated at a large academic center with institutional review board approval. Clinical, histologic and treatment characteristics, as well as disease outcomes were obtained from the electronic medical record. Results: Ten patients diagnosed with GBM-PNC were identified in the period of 2005-2019. Median follow-up was 17 months. Overall, 80% of patients were men, median age was 49 years (range 20-64) and ECOG 0-1. Fifty percent of patients received CSI as opposed to involved field radiation therapy (IFRT). Four of five patients receiving CSI were treated with proton therapy. All patients, but one received concurrent Temozolomide. Both IFRT and CSI were tolerated well with minimal grade 3-4 toxicities. Patients treated with CSI were more likely to experience transient grade 3-4 lymphopenia (60% vs 0%). Eighty percent of patients experienced a recurrence after treatment with median progression free survival (PFS) of 13 months (range 8-26). PFS did not differ between patients receiving IFRT and CSI (14 vs 12.5 months, p = 0.9). Median overall survival (OS) was 30 months for patients who received IFRT, and median OS was not reached in the CSI group. Of the patients who received CSI as part of their treatment, all recurrences were within the high dose radiation area. On the contrary, 75% of patients who received IFRT experienced multiple recurrences at new intracranial sites and later in the leptomeninges or the spine, requiring multiple treatment courses. Conclusions: This hypothesis generating study demonstrates that CSI may prevent distant intracranial metastasis and LM disease progression. CSI delivered with proton therapy was well tolerated with minimal additional toxicity. A larger study is needed to guide the optimal treatment of patients diagnosed with glioblastoma with primitive neuronal component.
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.
Quantification of immune cell-mediated destruction of tumor cells in vitro using the RNA disruption assay.
Authors: Pascheto Isabella , Pritzker Laura B , Kumar Aseem , Parissenti Amadeo Mark
Published: May 2020

e15017

Background: Immune checkpoint inhibitors (ICIs) are increasingly being used in the treatment of human cancers, often in combination with cytotoxic chemotherapy drugs. However, current ICIs are costly and are only effective against a fraction of patient tumours. Thus, a tool that could reliably quantify tumour response to ICIs and predict outcome post-treatment would be highly valuable. Patients with non-responding tumours could be spared the costs and toxic side-effects of the ineffective drugs and moved promptly to alternate treatments. We have observed that a variety of structurally and mechanistically distinct chemotherapy agents induce the degradation of ribosomal RNA (rRNA) into a large number of high molecular weight fragments (between the 28S and 18S rRNAs)---a phenomenon we have termed “RNA disruption”. High tumour RNA disruption during treatment, as quantified using the RNA disruption assay (RDA), has been shown to predict pathologic complete response and improved disease-free survival in breast cancer patients. Methods: To assess whether RDA could be used to monitor immune cell killing of tumour cells, we collected peripheral blood mononuclear cells (PBMCs) from consenting healthy human donors and enriched the cell population for natural killer (NK) cells to 90% using a negative selection approach. The cells, with or without IL-2 pre-treatment, were incubated with K562 cells, after which K562 cell killing was quantified over time using a standard immunocytotoxicity assay and K562 cell RNA disruption was measured using RDA. Results: Freshly isolated human NK cells when incubated with K562 chronic myeloid leukemia cells induced cell destruction and RNA disruption in K562 cells in a dose-dependent manner. Pre-incubation with IL-2 augmented both NK cell-mediated RNA disruption and NK-mediated cytotoxicity in K562 cells. Interestingly, the pattern of K562 RNA disruption fragments generated by NK cells was similar to that generated by chemotherapy drugs. Conclusions: RDA was successfully used to quantify immune cell-mediated destruction of tumour cells, raising the prospect of its possible use to monitor tumour destruction by immune cells in vivo and to predict response to ICIs (alone or in concert with cytotoxic chemotherapy drugs).
Platelets impact the responsiveness of immune checkpoint blockade therapy in solid tumors.
Authors: Riesenberg Brian P , Li Mingjia , Spakowicz Daniel , Hoyd Rebecca , Beane Joal , Yang Yuanquan , Oezkan Filiz , He Kai , Patel Sandip H. , Johns Andrew , Grogan Madison , Miah Abdul , Husain Marium , Bertino Erin Marie , Otterson Gregory Alan , Kendra Kari Lynn , Presley Carolyn J , Carbone David Paul , Li Zihai , Owen Dwight Hall
Published: May 2020

e15023

Background: A growing body of evidence has linked platelets (plts) with immune suppression in the tumor microenvironment (TME). Our group has demonstrated, plts are the dominant source for TGF-β in TME and pharmacologic inhibition of plt function enhances multiple forms of immunotherapy (Sc Immunol 2017 PMID 28763790; J Immunol 2019 PMID 31358658; Sci Transl Med 2020 PMID 31915300). To further delineate this relationship, we examined the roles of plts on T cell exhaustion in a preclinical model and on response to immune checkpoint inhibitors (ICI) in a large cohort of patients (pts) with stage 4 cancers. Methods: The mouse MC-38 colon adenocarcinoma model was used in age-matched female C57Bl/6J mice. Antiplatelet therapy (APT) consisting of aspirin and clopidogrel (both at 30 mg/kg daily) was delivered p.o. and anti-PD-1 antibody (100 mg/mouse every 3 days) was administered i.p. starting on days 5 and 9 respectively. TME analysis via multispectral histology or flow cytometry was performed. Retrospective analysis was carried out on 826 pts who received ICI from 2011-2017 at the Ohio State University. Baseline plt count was collected within 7 days before initiating ICI. Repeat plt count was obtained prior to initiation of cycle 2. Normal plt counts were defined as 150,000 – 450,000/µl blood, and thrombocytosis as plt ≥450,000/µl blood. Kaplan Meier and log-rank analysis were performed to estimate median survival and determine the association with plt count. Results: In pre-clinical models, pretreatment with APT (1) synergized with PD-1 blockade to enhance T cell infiltration into MC-38 tumors resulting in immediate tumor reduction, and (2) decreased tumor infiltrating CD8+ T cell TOX expression, a transcription factor associated with T cell exhaustion (Nat Immunol 2019 PMID: 31427776). Among pts receiving ICIs, 46 (5.6%) pts with thrombocytosis had a significantly reduced median OS vs pts with normal plt counts: 6.0 (95 CI: 1.5—10.6) months (mos) vs 11.6 (95 CI: 9.7—13.4) mos (p = 0.002). Fluctuations ≥50,000 plt/mL in either direction between cycle 1 and 2 were associated with a significant reduction in median OS: 8.3 (95 CI: 6.4—10.1) mos vs 13.6 (95 CI: 11.2-16.1) mos (p < 0.001). Conclusions: There is a strong association between plts and failure of ICI in both the preclinical and clinical settings, likely via modifying the amount of active CD8+ T cells infiltrating into tumors. These findings merit further study to delineate the underlying mechanism for plt-mediated immune suppression and strategies to overcome it.
hPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.
Authors: Chauhan Aman , Prieur Alexandre , Kolesar Jill , Arnold Susanne M. , Payen Léa , Lescuyer Gaelle , Liaud Pierre , Cousin Thierry , Sands Madison , Napier Dana , Evers Mark B , Joubert Dominique , Anthony Lowell Brian
Published: May 2020

e15038

Background: Neuroendocrine neoplasms (NENs) are heterogeneous tumors which originate from various organs and are of variable aggressiveness based on grade and morphology. Current biomarkers for NENs lack sensitivity and specificity, especially for high-grade NENs (small and large cell neuroendocrine carcinomas). hPG80, progastrin, is a novel bio-marker which is easily measured in plasma using an ELISA test. Physiologically, hPG80, an 80 amino acid protein, is the precursor of the gastrointestinal hormone gastrin. It is synthetized by gastric antrum G cells, and then processed into gastrin by multiple enzymatic processes. In pathological conditions, the GAST gene, which encodes hPG80, was shown to be over-expressed in human solid tumors from various primary sites. hPG80 is unprocessed and released from the tumor cells and becomes detectable in the blood. This study is the first to explore hPG80 in NENs. Methods: hPG80 was quantified in the plasma from 31 NEN patients using DxPG80 technology (ECS-Progastrin, Switzerland). Additional 69 samples are currently undergoing analysis. Progastrin concentrations in 18-70 YO (n = 557) and 18-25 YO (n = 137) healthy blood donors were compared to 31 stage IV NENs patients. The study was IRB approved. Results: Current data are for 31 patients. Data on total 100 patients will be presented at ASCO 2020. Mean age of study cohort at the time of blood collection was 60.9 years. 21 patients had grade 1 and 2 well differentiated NET. 10 patients had high grade NEN (Small cell, large cell and poorly differentiated NEC). High grade sub cohort also included two well differentiated grade 3 NET patients. Mean hPG80 in NENs was 14.17 pM as compared to 2.04 pM and 0.99 pM in 18-70 and 18-25 YO control groups (p < 0.0001), respectively. Subgroup analysis of NENs revealed mean hPG80 of 24.61 pM in high-grade NENs (n = 10) vs 10.88 pM in G1/2 NETs (n = 21). Conclusions: This first-ever study of plasma hPG80 in NENs suggests hPG80 may be a diagnostic blood-based biomarker in both low and high-grade NENs and further study is warranted. A prospective trial is ongoing in high-grade NEN to evaluate its role in monitoring of disease (NCT03958045) and further studies in low-grade NETs are underway. This research was supported by Cancer Center Support Grant (CCSG) from the National Cancer Institute (P30 CA177558) and ECS Progastrin.
Plasma cell free PD-L1 RNA expression correlated with tissue PD-L1 immunohistochemical staining and tumor mutation burden in non-small cell lung cancer.
Authors: Walker Paul R. , Bowling Mark , Sharma Nitika , Namireddy Praveen , Parent Teresa , Cherry Cynthia R. , Yeh Chen-Hsiung
Published: May 2020

e15049

Background: Programmed death ligand-1 (PD-L1) protein expression by immunohistochemical staining (IHC) correlates with response to immune checkpoint inhibitor (ICI) therapies in non-small cell lung cancer (NSCLC). Tumor mutational burden (TMB) is another immune biomarker of ICI response in NSCLC. Clinical studies indicate tissue PD-L1 protein expression and TMB are independent yet complementary. Both are limited by tissue acquisition and potential heterogeneity. Plasma cell free PD-L1 RNA (cfRNA) levels and tissue protein PD-L1 expression and TMB was analyzed and correlated in patients with advanced NSCLC. Methods: Patients with advanced NSCLC underwent complementary plasma and tissue next generation sequencing (NGS) with immune biomarkers prior to treatment. Plasma PD-L1 cfRNA was assessed by the Circulogene proprietary direct-on-specimen enrichment technology NGS platform. Correlating tissue testing was performed by the Caris Molecular Intelligence platform with the anti-PD-L1 22C3 IHC antibody and TMB measuring the total number of non-synonymous somatic mutations per megabase. Results: 107 patients with advanced NSCLC were evaluated with simultaneous plasma and tissue NGS testing. 17% (95% confidence interval [CI] 10-24%) patients plasma PD-L1 positive. 48.5% (CI 38-57%) tissue IHC PD-L1 positive. 7 of 18 plasma PD-L1 positive patients were tissue PD-L1 negative. 48% (CI 39-58%) total patients TMB ≥ 10 mutations per megabase (TMB high). Correlating TMB high in 72% (CI 50-94%) of plasma PD-L1 positive and 56% (CI 42-69%) of tissue PD-L1 positive patients. TMB high in 49% (CI 37-59%) plasma PD-L1 negative and 50% (CI 35-65%) tissue PD-L1 negative patients. Conclusions: Although less frequent than tissue PD-L1 protein expression, plasma PD-L1 cfRNA expression correlated with a higher association of tissue TMB high findings than tissue PD-L1 positive patients. There was not any TMB high difference between plasma PD-L1 negative and tissue PD-L1 negative patients. Over one-third of plasma PD-L1 positive patients were tissue PD-L1 negative. Clinical correlation with immune checkpoint inhibitor therapies is ongoing.