bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune profiling and clinical outcomes in patients treated with ramucirumab and pembrolizumab in phase I study JVDF.
Authors: Herbst Roy S. , Arkenau Hendrik-Tobias , Calvo Emiliano , Bendell Johanna C. , Penel Nicolas , Fuchs Charles S. , McNeely Samuel , Rasmussen Erik R , Wang Hong , Oliveira Joana M , Ferry David Raymond , Chau Ian 
Published: May 2020

3089 Background: In Study JVDF (NCT02443324), we combined ramucirumab (VEGFR2 antagonist) and pembrolizumab (PD-1 antagonist) to simultaneously target the tumor microenvironment and immune checkpoints in patients with advanced non-small cell lung cancer (NSCLC), gastric or gastroesophageal junction adenocarcinoma (G/GEJ), urothelial carcinoma (UC) or biliary tract cancer (BTC). We reported that this combination was associated with increased antitumor activity in patients with PD-L1 positive tumors by immunohistochemistry (IHC) compared with PD-L1 negative tumors.1) Here we explore the association between baseline gene expression profiles and clinical outcomes. Methods: JVDF was a nonrandomized phase 1a/b trial that treated patients with intravenous ramucirumab at 8 mg/kg on days 1 and 8 (G/GEJ, BTC) or 10 mg/kg on day 1 (G/GEJ, NSCLC, UC) plus pembrolizumab (200 mg day 1) every 3 weeks.1 Baseline tumor samples from 53 patients across 7 study cohorts were analyzed with the NanoString PanCancer Immune Profiling Panel for RNA expression and the DAKO PD-L1 IHC 22C3 pharmDx assay for PD-L1 protein expression. Clinical outcomes included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results: Across cohorts, PD-L1 gene expression was correlated with increased IFNγ gene expression and immune-related gene signatures (T effector, T cell-inflamed (TIS)), and trended with PD-L1 protein expression. Expression of immune checkpoint-related genes and myeloid-derived suppressor cell /regulatory T cell markers was increased in the NSCLC TPS≥50% PD-L1 IHC subgroup (N=8), while no clear pattern of expression was observed in other cohorts. Higher T effector and TIS scores appeared associated with better survival and response in NSCLC cohorts (mean TIS: 1.21±0.80 in responders (N=7) vs -0.13±0.57 in non-responders (N=7); p=0.004), and a trend was observed in G/GEJ cohorts (mean TIS: -0.18±0.30 (N=5) vs -0.39±0.21 (N=13); p=0.207). Of note, partial responses and stable disease were also observed in NSCLC and G/GEJ patients with a low baseline inflammatory signature score. Additional analyses are ongoing and will be presented. Conclusions: Baseline PD-L1 gene and protein expression tends to correlate with immune-related gene expression, and an inflamed tumor microenvironment may be associated with better clinical outcomes with ramucirumab and pembrolizumab. However, interpretation is limited by lack of control arm and sample size.1) Herbst et al. Lancet Oncol. 2019 Aug; 20 (8):1109-1123. Clinical trial information: NCT02443324 .
Gut microbiome to predict efficacy and immune-related toxicities in patients with advanced non-small cell lung cancer treated with anti-PD-1/PD-L1 antibody-based immunotherapy.
Authors: Hakozaki Taiki , Richard Corentin , Okuma Yusuke , Derosa Lisa , Elkrief Arielle , Zitvogel Laurence , Routy Bertrand , Hosomi Yukio 
Published: May 2020

3095 Background: The gut microbiome (GM) plays an important role in shaping systemic immune responses. Preclinical and clinical data suggest that GM influences anti-PD-1/PD-L1 or -CTLA-4 Antibody (Ab)-mediated anti-cancer responses. Furthermore, there is strong evidence that antibiotics (ATB) worsen clinical outcomes based on multiple retrospective and one prospective studies using immune checkpoint inhibitor (ICI). However, whether GM profiling, at baseline or post-ATB, could represent a biomarker of response in advanced non-small cell lung cancer (NSCLC) during ICI therapy remains unknown. Methods: We prospectively collected baseline (pre-ICI) fecal samples and clinical data Japanese patients (pts) with NSCLC treated with anti-PD-1/PD-L1 Abs in first or second-line therapy. We performed a 16S rRNA V3-V4 sequencing of gene amplicons of fecal microbes. Amplicon sequence variants were generated with dada2 R package. Diversity analysis was performed with phyloseq R. Differential abundance analysis was performed with both LEfSe and DESeq2 methods. Clinical endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and immune-related adverse events (irAE). Results: 70 fecal samples were analyzed. Median OS and PFS in all patients were 16.1 and 5.2 months, respectively. 16 pts (23%) were exposed to ATB 1 month prior to ICI initiation. Pts on ATB had lower α-diversity at baseline and underrepresentation of Clostridiales and Ruminococcaceae UCG 13. When analyzing ATB-free pts, lower α-diversity was observed in non-responders. In addition, Ruminococcaceae UCG 13 was enriched in patients with OS > 12 months, favorable ORR, and PFS > 6 months. Clostridiales order was also enriched in patients with OS > 12 months. Compositional GM differences were also observed between the patients who experienced clinically significant (≥grade 2) irAE; Lactobacillaceae and Raoultella were enriched in pts who had no significant irAE. Conclusions: We demonstrated the negative influence of ATB on GM composition and identified differential bacteria repertoire in pts experiencing favorable clinical outcomes or low grade irAE. Our data pave the way to the development of diagnosis tools aimed at identifying gut dysbiosis to predict resistance or irAE during ICI for NSCLC.
Immune activation in first-in-human anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) phase I/II MATINS trial: Part I dose-escalation, safety, and efficacy results.
Authors: Bono Petri , Virtakoivu Reetta , Vaura Felix , Jaakkola Panu , Shetty Shishir , Thibault Alain , de Jonge Maja J.A. , Minchom Anna Rachel , Ma Yuk Ting , Yap Christina , Robbrecht Debbie , Pasanen Annika , Skytta Tanja , Cruz Romillie , Jalkanen Markku , Jalkanen Sirpa , Mandelin Jami , Karvonen Matti , Koivunen Jussi , Hollmen Maija 
Published: May 2020

3097 Background: The scavenger receptor CLEVER-1 mediates the clearance of “unwanted” self-components and is highly expressed on tumor associated macrophages (TAMs). CLEVER-1 expression is associated with immunotherapy resistance and poor survival in several cancers. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8 T cell responses with robust anti-tumor activity. Targeting CLEVER-1 could therefore overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. Methods: The MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced cancers including immunotherapy-refractory melanoma, cholangiocarcinoma, hepatocellular carcinoma, ovarian cancer, colorectal (CRC), and pancreatic ductal adenocarcinoma. Part 1 consisted of a dose escalation phase; 30 pts (median age 65, range 30-81) were enrolled to examine 5 dose levels (0.1, 0.3, 1.0, 3.0, 10 mg/kg), to determine the optimal dose of FP-1305 for Parts 2 and 3. Two-stage time-to-event continual reassessment method (TITE-CRM) was utilized for the dose escalation in Part 1. Pts received 1-8 cycles (median 3) of FP-1305 Q3w. FP-1305 was well tolerated without dose-limiting toxicities. A consistent increase in blood NK cells, CD8/CD4 T cell ratio, B cells and a decrease in regulatory T cells was demonstrated. FP-1305 dosing led to the activation (CD25+) and Th1 skewing (CXCR3+) of T cell populations including increase in effector CD8 T-cells with downregulation of several inhibitory immune checkpoint molecules (PD-1, PD-L1, CTLA-4, and LAG3). Increased circulating IFNɣ levels were detected, with the highest levels in a heavily pretreated metastatic, microsatellite stable (MSS) colorectal cancer patient leading to a partial tumor response (-52%). FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response especially in non-inflamed tumors. Full safety, pharmacokinetic and efficacy results of MATINS trial (Part 1) will be presented for the first time in a final late breaking abstract. Clinical trial information: 2018-002732-24 .
Open-label, phase I study evaluating feasibility and safety of subcutaneous IMP321 (LAG-3Ig fusion protein, eftilagimod alpha) combined with avelumab in advanced stage solid tumor entities: Results from stratum D of the INSIGHT platform trial.
Authors: Goetze Thorsten Oliver , Mueller Daniel Wilhelm , Rafiyan Mohammad-Reza , Kiselicki Dragan , Eickhoff Regina , Jaeger Elke , Al-Batran Salah-Eddin 
Published: May 2020

3099 Background: Stratum D of the INSIGHT study investigates the feasibility and safety of s.c. application of IMP321 (eftilagimod alpha) combined with the PD-L1 inhibitor avelumab in advanced stage solid tumors. The MHC class II agonist IMP321 activates antigen-presenting cells followed by CD8 T-cell activation. The addition of avelumab aims at enhancing activity by combining IMP321’s activating effects on immune cells with the release of immune inhibitory effects caused by interruption of the PD-1/PD-L1 axis. Methods: This investigator-initiated phase I trial consists of four strata: intratumoral (A) or intraperitoneal IMP321 (B); s.c. IMP321 with SOC (C) or with PD-L1 inhibition (D). This abstract focuses on Stratum D. Patients (pts) receive 800mg avelumab i.v. q2w along with s.c. IMP321 injections (6mg IMP321 in cohort 1 and 30mg IMP321 in cohort 2). 12 pts are planned in stratum D : 6 pts in cohort 1 and 6 pts in cohort 2. Primary endpoint is safety. Results: So far, 8 pts have been enrolled (6 in cohort 1 and 2 in cohort 2). In 6 pts (cohort 1) treated for different tumor indications (gastric, gallbladder, colon cancer, pleural mesothelioma), no dose limiting toxicities occurred. 3 serious adverse events (SAEs) (1 acute kidney injury grade 5 in 1 pt, 2 preileus grade 3 in 1 pt) were reported, none of them was related to any of the study drugs. In total, 34 adverse events (AEs; grade 1-2, 21; grade 3, 12; no grade 4; grade 5, 1) have been documented in 5 pts. Most common grade 1-2 AEs were pain, nausea, and injection site reaction in 50%, 33%, and 17% of the pts. Most common grade 3 AEs were nausea/vomiting, preileus/ileus, and ascites in 33%, 33%, and 17% of the pts. One AE grade 5 (acute kidney injury) was reported. 4 AEs grade 1-2 were possibly or definitely related to IMP321 (injection site reaction 2x; fever; lipohypertrophy), 6 AEs grade 1-2 were possibly or definitely related to avelumab (nausea 2x; chills; fever; dyspnea; lipohypertrophy). All AEs grade 3-5 were unrelated to any of the study drugs. Of the 8 pts enrolled so far, 4 had disease progression (acc. to RECIST 1.1), 1 partial response, 1 stable disease with some extent of tumor shrinkage, and 2 have not had tumor assessment yet. Conclusions: Combination treatment with avelumab 800mg and IMP321 6mg is safe and well tolerated. Cohort 2 will be presented at the meeting. Clinical trial information: NCT03252938 .
Deep learning-based predictive imaging biomarker model for EGFR mutation status in non-small cell lung cancer from CT imaging.
Authors: Mahajan Abhishek , Kania Vatsal , Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Menon Nandini Sharrel , Kumar Rajiv , Rane Swapnil , Chougule Anuradha , Vaidya Suthirth , Prabhash Kumar 
Published: May 2020

3106 Background: Deep learning based radiogenomic (DLR) models present a promising performance in assisting lung cancer care. The purpose of this study was 1) To develop and validate DLR signatures to predict the EGFR mutation, 2) To assess the incremental value of these DLR signatures in comparison to the traditional clinical and semantic features. Methods: 223 patients were selected from two phase III randomized trials in patients with advanced non-squamous NSCLC with EGFR-sensitizing mutation and EGFR wild type who were planned to receive palliative therapy (trial 1: gefitinib or gefitinib plus pemetrexed and carboplatin and trial 2: pemetrexed maintenance and erlotinib maintenance). Our method is an end-to-end pipeline that requires only the manually selected tumour region in a CT image without precise tumour boundary segmentation or human-defined features. Two deep convolutional neural networks with 3D U-Net architectures are trained to segment lung masses and nodules from 3D regions of the CT image. The primary end point was EGFR prediction using Radiomics and DLR pipeline. We also compared the performance of combination of models in predicting the mutational status. Results: A total of 223 patients (mean age, 54.18 years; age range, 28–80 years) were included in this study. There were 121 (54.3%) patients with EGFR mutation and 102 (45.7%) patients who were EGFR wild type. On multivariate logistic regression analysis, Clinical variable and CT semantic features that were found to be significantly associated EGFR mutation were tumor stage, smoking status, pure solid texture, presence of non-tumor lobe nodule, and average enhancement. For predicting EGFR mutation, ROC curve plotted with clinical variables model, CT semantic variables model, Radiomics model, DLR model showed an AUC value of 0.70, 0.73, 0.94, 0.72 respectively. Clinical variables and semantic features were added to the radiomics predictive model and deep learning predictive model independently, showed further improvement in the accuracy for either model from AUC 0.94+/-0.02 to 0.96+/-0.02 and from AUC 0.72+/-0.02 to 0.82+/-0.04 respectively. Conclusions: The radiomics and DLR model by machine-learned information, extracted from CT images without precise manual segmentation, could predict EGFR mutation with very high accuracy. This AI based model can be used as non-invasive and easy-to-use surrogate imaging biomarker for EGFR mutation status prediction. Clinical trial information: CTRI/2018/10/022102 .
GEN-009, a neoantigen vaccine containing ATLAS selected neoantigens, to generate broad sustained immunity against immunogenic tumor mutations and avoid inhibitory peptides.
Authors: Cohen Roger B. , Twardowski Przemyslaw , Johnson Melissa Lynne , Gillison Maura L. , Stein Mark N. , Vaishampayan Ulka N. , McNeil Lisa , Shainheit Mara , DeOliveira Daniel , Jain Manish , Price Jessica , Hernandez Richard , DeCillis Arthur P. , Singh Narinderjeet , Flechtner Jessica , Davis Thomas A. 
Published: May 2020

3107 Background: Tumor-specific neoantigens provide personalized targets for immunotherapy. Vaccines against epitopes predicted by in silico approaches very rarely induce CD4+ and CD8+ ex vivo T cell responses regardless of formulation. ATLAS selects neoantigens for vaccine inclusion using ex vivo screening of all patient-specific mutations to identify pre-existing CD4+ or CD8+ T cell responses and to exclude Inhibigens, which are inhibitory peptides that suppress immunity and accelerate tumor progression. The Inhibigen burden correlates with patient outcomes in observational studies and rapid tumor progression in mouse models. Methods: GEN-009-101 is a phase 1/2a study testing safety, immunogenicity and clinical activity in immune responsive tumors. After next-generation tumor sequencing and ATLAS testing of autologous leukocytes, up to 20 stimulatory synthetic long peptides adjuvanted with poly-ICLC comprise each personalized vaccine. Eight vaccinated patients have been followed for sustained immunological responses and clinical outcomes. Results: The 40 doses given across patients have induced only mild local discomfort and no DLT. Vaccination has generated immune responses against 99% of administered peptides, with both CD8+ and CD4+ responses in ex vivo fluorospot assays. To date, no patients have developed recurrent disease. Broad immunity develops as early as Day 29 and is sustained for over 12 months. Immune response against individual peptides is correlated with peptide concentration (OR = 1.26, p≤0.0001) but not with other classifiers such as GRAVY index (Grand Average of Hydropathy), tumor type, injection site or sex. The Inhibigen burden prior to treatment again correlates with disease progression. Conclusions: GEN-009 identifies tumor specific immune targets from the individual patient’s tumor mutagens. Initial clinical data show that ATLAS antigen selection may be critical to the induction of broad, rapid and sustained immunity against tumor specific neoantigens. Clinical vaccination with PD-1 blockade is in process. Clinical trial information: NCT03633110 . [Table: see text]
Evidence of intratumoral localization, activation, and immunomodulatory effect of CX-072, a probody therapeutic targeting PD-L1, in a phase I/II trial.
Authors: Lyman Susan , Naing Aung , Zein Ivan Adiputra , Howng Bruce , Winter Michael B. , Vasiljeva Olga , Garner William , Zheng Beiyao , Stroh Mark , Kavanaugh W Michael , Desnoyers Luc Roland ,   for the PROCLAIM-CX-072 Investigators
Published: May 2020

3108 Background: PROBODY therapeutics (Pb-Tx) are masked antibodies designed to be selectively activated in the tumor microenvironment by tumor-associated proteases and to remain largely inactive in normal tissue. CX-072, a Pb-Tx directed against PD-L1, is designed to reduce the potential for immune-associated adverse events in normal tissues while maintaining anti-tumor activity. CX-072 is being investigated in PROCLAIM-CX-072 (NCT03013491), a first-in-human phase 1/2 trial. CX-072 is administered as monotherapy or in combination with ipilimumab to patients with metastatic or recurrent solid tumors or lymphomas for which approved PD-1/-L1–based therapy is not available. We present the updated results of a tissue-based biomarker program designed to assess activation, localization, and mechanism of action of CX-072 in patient tumors. Methods: Tumor biopsies were collected during the screening phase, and also 3–5 days after the first or third dose of 0.3–30 mg/kg CX-072. Tumor-associated protease activity was measured by tissue zymography. Intratumoral CX-072 activation was measured using capillary immunoelectrophoresis, and PD-L1 levels were measured by an ultrasensitive ELISA. Intratumoral CD8 expression was analyzed using immunohistochemistry. Intact and total CX-072 in plasma were measured by LC-MS/MS. Results: Twenty-six of 30 (87%) evaluable predose biopsies had detectable levels of relevant protease activity. Intratumoral activation of CX-072 was quantifiable in 3 of 8 (38%) biopsies from patients treated with CX-072 at 3 mg/kg and in 12 of 12 (100%) biopsies from patients treated with ≥10 mg/kg. In contrast, CX-072 remained predominantly in the intact form in circulation. The molar ratio of activated intratumoral CX-072 to total intratumoral PD-L1 ranged from ~14x to > 100x in patients dosed at 10 mg/kg, and the calculated tumor receptor occupancy for these patients was ≥99%, congruent with quantitative systems pharmacology model predictions. An increase in CD8+ T cells and elevation of cytotoxic T-cell markers was observed in the tumors of 11 of 18 (61%) CX-072 monotherapy patients, consistent with inhibition of the PD-L1 pathway. Conclusions: These results demonstrate that the Pb-Tx CX-072 behaves as designed in patients. Clinical trial information: NCT03013491 .
SBT6050, a HER2-directed TLR8 therapeutic, as a systemically administered, tumor-targeted human myeloid cell agonist.
Authors: Metz Heather , Childs Monica , Brevik Jamie , Winship Damion , Brender Ty , Comeau Michael , Moyes Kara , Chang Jenny , Adamo Jeffrey , Setter Ben , Xu Hengyu , Fan Li-Qun , Smith Sean , Tan Phil , DuBose Robert , Latchman Yvette , Baum Peter , Odegard Valerie 
Published: May 2020

3110 Background: Solid tumors are replete with myeloid cells which, when activated, drive potent anti-tumor responses. Clinical development of systemically administered myeloid cell agonists, however, has been hindered by acute toxicities due to peripheral activation of the targeted cell types. Intratumoral administration, the route of delivery typically used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. A systemically delivered myeloid cell agonist with tumor-localized activity has the potential to overcome challenges encountered with other innate immune/myeloid cell agonists in clinical development. Methods: SBT6050 is a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist payload conjugated to a HER2-directed monoclonal antibody. Delivery of the payload into the endosome of human myeloid cells, where TLR8 resides, requires the co-engagement of HER2 on tumor cells and Fc gamma receptor on human myeloid cells. Thus, SBT6050 is designed for systemic delivery and tumor-targeted activation of human myeloid cells. Results: Studies with human immune cells show that SBT6050 potently induces, in a HER2-dependent manner, multiple anti-tumor immune activities due to its direct activation of myeloid cells and the subsequent induction of T and NK cell cytolytic activity. SBT6050 is designed to activate human myeloid cells only in the presence of HER2-positive tumor cells with moderate (2+ by IHC) or high (3+ by IHC) expression levels. Tumor-localized activity has been demonstrated in mouse models using a SBT6050 mouse surrogate. Systemic delivery results in robust single agent efficacy in multiple mouse tumor models, even those engineered to lack T cells, without accompanying peripheral cytokine production. Trastuzumab and SBT6050 bind to distinct epitopes on HER2 and enhanced activity is observed when the two agents are combined. Conclusions: SBT6050 is a systemically administered, tumor-targeted myeloid cell agonist that demonstrates single agent efficacy in multiple mouse tumor models without peripheral cytokine production. A first-in-human study with SBT6050 is expected to begin this year for patients with HER2-expressing solid tumors.