bluuebunny/crossref_metadata_2025 huggingface dataset:
A signal-seeking trial of olaparib and durvalumab in homologous repair-deficient tumors: A sub-study of the cancer molecular screening and therapeutics (MoST) program.
Authors: Joshua Anthony M. , Prawira Amy , Thavaneswaran Subotheni , Cosman Rasha , Lee Chee Khoon , Sjoquist Katrin Marie , Simes John , Thomas David Morgan , Espinoza David , Sebastian Lucille , Ballinger Mandy L. , Hague Wendy , Chinchen Sarah , Collignon Emily , Kansara Maya , Palacios Talia , Grady John , Barker Hayley , Thornton Keith
Published: May 2020

3073

Background: Data on the utility of a PARP inhibitor in combination with a checkpoint inhibitor remain limited, particularly in the histology agnostic setting with homologous recombination deficiency (HRD). This study evaluated the clinical activity of the combination of olaparib and durvalumab with the primary study endpoint of progression-free survival (PFS) at 6 months (PFS6m). Methods: This was a phase II, single-arm, signal-seeking study of the MoST program. Patients were recruited into two cohorts based on HRD genes, agnostic to histology: (1) BRCA 1/2 deficient tumours, excluding breast, prostate, ovarian cancers, and (2) other HRD related genes. Molecular testing was performed using in-house and commercial panels on archival tumour tissue centrally adjudicated by a molecular tumour board. All patients were treated with olaparib 300mg bid for 1 month, followed by combination with durvalumab 1500mg q4 weekly for 13 cycles. Olaparib treatment was then continued until disease progression. Results: Between Nov 2017-Feb 2019, 48 patients were enrolled (16 to BRCA 1/2 cohort 1 and 32 to HRD related genes cohort 2). Most common tumour sites were bone/soft tissue (15%, N=7), pancreas (13%, N=6) and stomach (8%, N=4). Overall best response in cohort 1 was PR (25%, N=4) and SD 4 (25%, N=4), and cohort 2 was PR (6%, N=2) and SD (56%, N=18). Median PFS was 3.65m (Cohort 1) and 3.56m (Cohort 2) respectively. PFS6m was 35% (Cohort 1) and 38% (Cohort 2) respectively. PDL1 status was not predictive of olaparib and durvalumab benefit. The most common grade 3/4 adverse events were anemia (11%%, N=4), abdominal pain (9%, N=3), increased lipase (9%,N=3), increased amylase (9%, N=3), dyspnea (6%, N=2), Hyperglycemia dyspnea (6%, N=2), Pancreatitis dyspnea (6%, N=2) and hematuria (6%, N=2). Conclusions: Olaparib and durvalumab show promising activity in a histology agnostic setting, particularly in BRCA deficient tumours. Further research is needed to identify biomarkers that correlate with treatment benefit. Results from longer clinical follow-up and additional biomarker analyses will be presented. Clinical trial information: ACTRN12617001000392 .
Success and failure of additional immunosuppressants in steroid-refractory pneumonitis related to immune checkpoint blockade.
Authors: Beattie Jason , Fuentes Paige , Rizvi Hira , Luo Jia , Schoenfeld Adam Jacob , Postow Michael A. , Callahan Margaret K. , Warner Allison Betof , Chawla Mohit , Hellmann Matthew David
Published: May 2020

3078

Background: Severe immune related adverse events (irAEs) with immune checkpoint blockade are uncommon but can be fatal. Steroids are the most common initial treatment for most non-endocrine irAEs, but some patients are or become refractory to steroids. When steroids are not effective, there is limited data to guide management strategies, particularly in the context of pneumonitis. Methods: All patients at MSK treated with immune checkpoint blockade from 2013-2020 were queried for receipt of an immunosuppressant (e.g. TNF antagonists, mycophenolate mofetil, cyclophosphamide) beyond steroids. Patient records were then manually reviewed to identify patients who received such therapy for management of immunotherapy-related pneumonitis. Results: Among 5363 patients treated with immune checkpoint blockade, 364 (6.8%) received an additional immunosuppressant for an irAE, including 28 (0.5% of all patients treated) patients treated for pneumonitis. Most of these pneumonitis events (19/28, 68%) were grade 3 or higher. Agents used included mycophenolate mofetil (7/28; 25%), TNF antagonists (23/28; 82%), and cyclophosphamide (1/28; 3.5%); more than one medication was used in 3 patients (11%). The indications were primary non-response to steroids (n = 16, 57%) and recrudescence after initial response to steroids (n = 12, 43%). At 90 days from initiation of the additional immunosuppressant, 13/28 (46%) patients were alive with improvement or resolution of pneumonitis while 15/28 (54%) had died. Survival with resolution/improvement was more common in patients treated for recrudescence vs primary non-response (67% vs 25%, p = 0.05). Conclusions: Outcomes with additional immunosuppressants in the setting of steroid-refractory immune-related pneumonitis are poor, but resolution can occur in some cases. A deeper understanding of the mechanistic underpinnings of irAEs is needed to more effectively tailor immunosuppressant therapies, particularly in severe pneumonitis events.
Association of a STK11/KEAP1-mutation gene expression signature in lung adenocarcinoma with immune desertion in squamous cell carcinomas and mediation by NFE2L2 deregulation.
Authors: Rieke Damian Tobias , Klinghammer Konrad Friedrich , Obermayer Benedikt , Blanc Eric , Messerschmidt Clemens , Jöhrens Korinna , Klauschen Frederick , Tinhofer Inge , Beule Dieter , Keilholz Ulrich , Ochsenreither Sebastian
Published: May 2020

3082

Background: KEAP1 and STK11 mutations are associated with resistance to immune checkpoint inhibition (ICI) in non-small cell lung cancer (NSCLC). Mechanisms are currently unknown. Methods: We examined mutation, methylation, copy number and gene expression data from the cancer genome atlas (TCGA) lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC), head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma (CESC) data sets as well as public single cell gene expression data from a HNSCC cohort. Pathway annotations were performed using gene set enrichment analysis. A previously published cohort of NSCLC patients treated with ICI was analyzed for the predictive value of NFE2L2 mutations on PFS. Results: Annotation of STK11 and KEAP1 mutant LUAD revealed identical gene set enrichment for mitochondrial metabolism and downregulation of the STING-pathway, immune checkpoints, and interferon signaling. A STK11/KEAP1-mutation derived gene expression signature was established in LUAD and found to be driven by NFE2L2-regulated genes. This gene expression signature was independently predictive of immune desertion in LSCC, CESC and HNSCC and associated with STING-pathway downregulation in single cell sequencing analyses in HNSCC. KEAP1 and STK11 mutations were less frequent in LSCC, CESC and HNSCC but NFE2L2 mutations were identified in 15, 6 and 5%, respectively. NFE2L2 mutant SCC exhibited upregulation of the 15-gene- signature as well as immune desertion. In NSCLC, NFE2L2 mutations were associated with significantly worse PFS with ICI. Conclusions: Alterations of KEAP1, STK11, NFE2L2 and other related genes are linked to NFE2L2 target gene upregulation and immune desertion in LUAD, CESC, LSCC and HNSCC alike. The NFE2L2 pathway should be investigated clinically as a putative negative predictive biomarker for ICI and a potential therapeutic target.
A phase I/II study of GB1275, a first-in-class oral CD11b modulator, alone, and combined with pembrolizumab in specified advanced solid tumors or with chemotherapy in metastatic pancreatic cancer (KEYNOTE-A36).
Authors: Rasco Drew W. , Bendell Johanna C. , Wang-Gillam Andrea , Park Wungki , O'Reilly Eileen Mary , Zhou Lei , Galkin Anna , Carter Laura L , Nickle David , Li Jack , Ferguson Beatrice , Chaney Marya F. , Dupont Jakob , Messersmith Wells A.
Published: May 2020

3085

Background: GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) at the tumor site, repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. When combined with an anti-PD-1 antibody or chemotherapy, these immunomodulatory effects translated into potent anti-tumor effects and prolonged survival in orthotopic PDAC models [Panni RZ, et al. Sci Transl Med. 2019 Jul 3;11(499)]. This ongoing first-in-human study consists of dose escalation of GB1275 monotherapy (Regimen A), GB1275 + pembrolizumab (Regimen B), and GB1275 + nab-paclitaxel + gemcitabine (Regimen C), followed by Phase 2 expansion in newly diagnosed metastatic pancreatic, MSS colorectal, and PD-L1-positive gastric/GEJ cancers. Here we report interim results of the dose escalation portion of the trial. Methods: The dose escalation phase is based on a standard oncology phase 1, 3+3 design. Cohorts of 3 to 6 patients (pts) with histologically confirmed locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, prostate, or breast cancer were sequentially assigned to ascending dose levels of GB1275 taken orally twice daily (BID) in 1 of 3 regimens: Regimen A was initiated first; Regimen B commenced after completion of the first two cohorts of Regimen A, and Regimen C will be initiated when Regimen A is completed. Dose escalation was based on assessment of safety including dose-limiting toxicity (DLT). Serial blood and tumor samples were collected for pharmacokinetic (PK) and biomarker analyses. Results: As of January 21, 2020, 13 pts were treated, with 3 each in Regimen A (GB1275 100mg, 200 mg and 400 mg BID) dose levels and 4 in Regimen B with GB1275 100 mg BID + pembrolizumab. No DLTs have been reported. GB1275 treatment-related adverse events were reported in 5 pts; all were Grade 1 in severity. Preliminary PK analyses showed a mean elimination half-life of ~7 hours. Reduction in peripheral MDSCs was observed in the majority of pts with serial samples. Biomarker analysis in serial tumor tissue is ongoing. Conclusions: Preliminary data show minimal treatment-related toxicities with the studied regimens. PK data support BID dosing. Dose escalation is ongoing. Updated data will be presented. Clinical trial information: NCT04060342 .
Discovery of a novel shared tumor antigen in human lung cancer.
Authors: Tseng Diane , Chiou Shin-Heng , Yang Xinbo , Reuben Alexandre , Wilhelmy Julie , McSween Alana , Conley Stephanie , Sinha Rahul , Nabet Barzin , Wang Chunlin , Shrager Joseph B , Berry Mark F. , Backhus Leah Monique , Lui Natalie , Wakelee Heather A. , Neal Joel W. , Zhang Jianjun , Garcia K. Christopher , Mackall Crystal , Davis Mark
Published: May 2020

3087

Background: While there has been much attention on mutation-associated neoantigens in tumors, there is less known about non-mutated tumor antigens that are shared across individuals. Understanding tumor-infiltrating T cell recognition of shared tumor antigens is important for understanding cancer immune recognition and escape, and may reveal novel targets for therapy. Methods: We have established a novel approach for discovering shared tumor antigens in human lung cancer. This approach involves identifying candidate T cell receptor (TCR) alpha/beta pairs that are predicted to exhibit specificity for shared tumor antigens in the context of a given human leukocyte antigen (HLA). We then screen the T cell receptor for binding to yeast display libraries of peptide-HLA. The Mark Davis lab at Stanford has previously developed an algorithm that groups T cell receptors into antigen specificity groups based on shared motifs within the TCR complementarity-determining region 3 (CDR3) sequences. Leveraging a dataset of over 700K CDR3 sequences from 178 HLA-typed non-small cell lung cancer (NSCLC) patients, we have found up to 4,300 antigen specificity groups after applying stringent cutoffs. We sequenced TCR alpha/beta pairs from 15 patients with lung adenocarcinoma (n = 4,705). Results: We identified an antigen specificity group enriched in tumor compared to adjacent uninvolved lungs. Antigen screening of the T cell receptor belonging to this specificity group using an A02 yeast display libraries led to the identification of a dominant peptide after four rounds of enrichment. We functionally validated that the peptide derived from the protein TMEM161A stimulated Jurkat cells expressing the TCR alpha/beta receptor of interest. We show that full-length TMEM161A protein is processed and presented into a peptide that stimulates primary T cells expressing the TCR alpha/beta receptor. We observe that a peptide from Epstein-Barr virus (EBV) protein LMP2 also stimulated the same TCR alpha/beta receptor. We have show that TMEM161A RNA and protein are overexpressed in human lung cancer compared to adjacent uninvolved lungs. Conclusions: We have demonstrated a novel approach toward antigen discovery and identified a shared tumor antigen TMEM161A in human lung cancer.
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.
Characterization of NRG1 gene fusion events in solid tumors.
Authors: Jonna Sushma , Feldman Rebecca , Ou Sai-Hong Ignatius , Nagasaka Misako , Swensen Jeffrey , Korn Wolfgang Michael , Borghaei Hossein , Vanderwalde Ari M. , Lopes Gilberto , Nieva Jorge J. , Spira Alexander I. , Kim Edward S. , Liu Stephen V.
Published: May 2020

3113

Background: NRG1 fusions are actionable genomic alterations detected across tumor types. The NRG1 gene encode for neuregulin, which serves as a ligand for ERBB3 and ERBB4 receptors and activates downstream signaling through the MAPK and PI3K pathways. Here, we update the detection of NRG1 gene fusions across tumor types and further describe fusion characteristics. Methods: Samples submitted for clinical molecular profiling that included RNA-sequencing (Archer Dx or Caris MI transcriptome) were retrospectively analyzed for NRG1 fusion events. All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by NGS. Results: A total of 82 NRG1 fusion events (0.2% of 44,570) were identified. Among the fusions identified, the distribution across tumor types was as follows: non-small cell lung cancer (NSCLC, 54%), breast cancer (11%), ovarian cancer (7%), pancreatic cancer (7%), cholangiocarcinoma (6%), colorectal cancer (5%), and other (10%). Forty-two unique fusion partners were identified, the most common being CD74 (23%), ATP1B1 (9%), SLC3A2 (7%), RBPMS (6%) and SDC4 (4%). Almost half (47%) of all fusion events are expected to include the transmembrane domain contributed by the NRG1 fusion partner. Lung and pancreatobilliary cancers had the highest rates of transmembrane domain retention from their fusion partners (63.6% and 54.5%, respectively). In all other tumor groups, most fusion partners lacked transmembrane domains. In 15% of cases, the chimeric transcripts are predicted to lead to increased expression of NRG1. The most commonly reported breakpoints in NRG1 occur in exon 6 and exon 2. While fusions with the NRG1 breakpoint at exon 2 retain the immunoglobulin (Ig) domain and all downstream portions (including EGF-like domain), those at exon 6 do not contain the Ig portion and result in shorter chimeric proteins. The breakpoints in all CD74:NRG1 fusions, the most common fusions in NSCLC, occur at exon 5 or 6 and cause truncation of domains upstream of the EGF-like domain. In ATP1B1:NRG1 fusions, the most common fusions in pancreatobilliary cancers, the breakpoints are at exon 1 or 2 and retain the Ig domain. Conclusions: NRG1 fusion products are diverse across tumor types, but the significance of these variations is not clear. The biological and clinical implications of retaining certain domains of NRG1 (such as the Ig domain) and of fusion partners warrants further investigation.
Deep learning-based immune phenotype analysis reveals distinct resistance pattern of immune checkpoint inhibitor in non-small cell lung cancer.
Authors: Ock Chan-Young , Park Sehhoon , Yoo Inwan , Shin Jisoo , Lee Seungje , Lee Sarah , Paeng Kyunghyun , Choi Yoon La , Mok Tony S. K. , Lee Se-Hoon
Published: May 2020

3119

Background: Resistance pattern and biological mechanism of immune checkpoint inhibitor (ICI) has been poorly understood. Sine suggested resistance mechanisms would be either innate resistance caused by lack of immune recruitment or acquired immune evasion after durable response of ICI treatment, we hypothesized that resistance pattern of tumor microenvironment would be distinct according to duration of ICI response in non-small cell lung carcinoma (NSCLC). In the current study, we applied deep-learning-based classification of three immune phenotypes (3IP): inflamed, excluded, and desert, to objectively assess the immunologic status of tumor microenvironment. Methods: Deep-learning algorithm of H&E Whole-Slide Images (WSI), called Lunit-SCOPE, was trained with 1,824 H&E WSI of NSCLC from Samsung Medical Center (SMC). WSI was divided into patches and each patch (~10 high-power fields) was classified as inflamed, excluded and desert, based on both quantity and localization of immune cells. Among NSCLC patients treated with ICI in SMC, 87 paired treatment-naïve (Pre, patch N = 15,415) and post-progression (Post, patch N = 18,197) tumor tissues were analyzed for Lunit-SCOPE. Results: In 87-paired samples, proportions of excluded and desert phenotypes were increased in post-progression tumor tissues (excluded; Pre 26.8% versus Post 32.5%, desert; Pre 19.5% versus Post 25.3%). Focused on 29 patients classified as inflamed in treatment-naïve, proportion of immune phenotypes of post-progression were clearly different according to duration of response, divided by median progression-free survival (PFS) of 3.7 m. Patients with rapid progression without ICI response (PFS < 3.7 m) turned into desert type (46.2%), whereas durable responder (PFS ≥ 3.7 m) either still remained on inflamed phenotype (42.9%) or turned into excluded phenotype (21.4%). Patients who remained on inflamed phenotype had favorable overall survival after progression on ICI, compared to turned into desert type (median survival not reached versus 6.6 m, P= 0.0296). Conclusions: Resistance patterns of ICI are distinct according to duration of response in patients with inflamed phenotype. Rapid progressor turns off immune into desert phenotype whereas most durable responder keeps immune recruitment into tumor microenvironment, which needs tailored strategy to overcome ICI resistance.
Extrachromosomal DNA (ecDNA) carrying amplified oncogenes as a biomarker for insensitivity to pembrolizumab treatment in gastric cancer patients.
Authors: Christiansen Jason H. , Nguyen Nam-phuong , Verhaak Roel , Kim Hoon , Bafna Vineet , Mischel Paul , Hassig Christian
Published: May 2020

3123

Background: In the KEYNOTE-059 study, the anti-PD-1 checkpoint inhibitor pembrolizumab was shown to have a modest overall response of 11.6%. Common predictors of response including, high microsatellite instability (MSI-H), PD-L1 expression, tumor mutational burden (TMB) and tumor inflammation signature (TIS), were not individually sufficient for patient selection. Recent pancancer studies have highlighted a unique population of cancer patients whose tumors appear to be driven by oncogene amplifications on extrachromosomal DNA (ecDNA). These ecDNA-driven tumors are aggressive and characterized by high levels of genomic instability. We sought to understand if tumors that possess ecDNA may represent a subset of the patient group that is non-responsive to anti-PD-1 therapy. Methods: We determined the ecDNA status of gastric cancer patients (N = 108) using whole genome sequencing (WGS) from the TCGA Pan-cancer dataset These patients had been previously subtyped for EBV status, genomic stability (GS), microsatellite instability (MSI), and chromosomal instability (CIN). Patients that were ecDNA+ were re-classified into a set regardless of gastric subtype. Additionally, TMB, TIS, and PD-L1 expression levels were collected. Results: 32% of gastric cancer patients were positive for ecDNA signatures and mutually exclusive from the 23% of MSI-H patients. We found that ecDNA positive tumors had statistically significantly lower TIS than all other groups (p-value < 0.05) except CIN tumors (p-value = 0.09). The ecDNA positive tumors also had lower PD-L1 expression than all but GS tumors. Only MSI-H showed statistically significantly higher TMB scores compared to every other group (p-value < 0.001), no difference in TMB scores were observed between every other pair of groups. Conclusions: Patients whose tumors are ecDNA positive represent a unique population that display signatures for non-response to checkpoint inhibitor therapy, including MSS, low TIS, and PD-L1 expression. Thus, the determination of tumor ecDNA status may have utility as an additional patient selection strategy for checkpoint inhibitor therapy. As ecDNA are not limited to gastric cancers, this study highlights the importance of the development of a clinical diagnostic test for ecDNA status and the need for further research on ecDNA biology, its impact on immunotherapy response, and potential ecDNA-directed therapeutics
CIMAC-CIDC tissue imaging harmonization.
Authors: Akturk Guray , Parra Cuentas Edwin Roger , Lako Ana , Gjini Evisa , Espiridion Beatriz Sanchez , Wistuba Ignacio Ivan , Thurin Magdalena , Hewitt Stephen M. , Rodig Scott , Zhang Jiexin , Neuberg Donna S. , Lee J. Jack , Gnjatic Sacha , Tetzlaff Michael T. ,   CIMAC-CIDC Network
Published: May 2020

3125

Background: The Cancer Immune Monitoring and Analysis Centers Cancer Immunology Data Commons (CIMAC-CIDC) network is a NCI Cancer Moonshots initiative to provide state-of-the-art technology and expertise for immunotherapy clinical trials. Multiplex tissue immunostaining is an integral assay provided that examines density and spatial distribution of immune cells and markers in tissues, for their prognostic or predictive value. Two approaches were evaluated for sensitivity, specificity, and reproducibility and subsequently harmonized: chromogenic-based Multiplex Immunohistochemical Consecutive Staining on Single Slide (MICSSS) and Multiplex Immunofluorescence (mIF) based tyramide signal amplification system. Methods: Harmonization was performed across CIMACs (Mount Sinai, Dana Farber Cancer Institute, MD Anderson Cancer Center) in multiple steps to prove that comparable data can be generated independent of site and platform. Goals: 1) harmonize image analysis platforms alone using tissues pre-stained with single chromogenic IHC for CD3 (membrane), Ki67 (nuclear), and CD68 (cytoplasmic), 2) compare image acquisition platforms, 3) streamline Antibody (Ab) clones and assess PD-L1 detection in relation to CLIA- assays, 4) harmonize staining protocols, image acquisition, and analysis platforms on 2 test head and neck tumor samples using MICSSS and mIF, 5) validate harmonization results with a tissue microarray on 27 tissues representing multiple tumors. For last steps, each CIMAC used their platforms for PD-L1, PD-1, CD3, CD8, and pan-cytokeratin (PanCK) staining on one of three consecutive slides from serial sections and compared densities of each marker. Results: Variables as PD-1 Ab clone, positive control reference tissues, sigma value for nuclear segmentation, and use of machine-learning based cell classifier were found to be key to produce accurate, reliable, comparable data. After visual quality control assessment and comparisons of each Region Of Interest (ROI), an overall inter-site Spearman correlation coefficient of ≥0.85 was achieved per marker within each tissue and across tissue types (expect pan-Cytokeratin, ≥0.7), with average coefficient of variation ≤0.1. Conclusions: These results show for the first time that two platforms can deliver harmonized data, despite differences in protocols, platforms, reagents, and analysis tools. Data resulting from retrospective and prospective CIMAC-CIDC analyses may be used with confidence for statistical associations with clinical parameters and outcome.