Annals of Oncology

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161P Regulatory interacting network between the immunomodulatory non-coding RNAs: miR-17-5p, MALAT1 and H19 lncRNAs in modulating the tumour microenvironment in TNBC

AbstractBackgroundTriple-negative breast cancer (TNBC) patients are the least fortunate in terms of diagnosis, prognosis and treatment compared to other BC subtypes. Chemotherapy remains the standard treatment, with remarkable rate of resistance. Immunotherapy, on the other hand has shown promising approaches for this aggressive BC subtype. A critical determinant of the success of the immunotherapeutic approaches introduced recently in the clinics is the tumour microenvironment (TME). Our research group has recently highlighted the potential role of IL-10 in shaping the TME of TNBC patients. In this study, we focus on the main pro-inflammatory cytokine, tumour necrosis factor-α (TNF-α), in modulating TME in TNBC cells. In a more translational approach, ncRNAs have been casted as vital regulators of the immune system. A new frontier in the ncRNA world is the cross talk between miRNAs and lncRNAs. In this study, we aimed to investigate the role of microRNA-17-5p and its cross-talk with the oncogenic long non-coding RNAs: MALAT1 and H19 in regulating TNF-α in the TME of TNBC.MethodsForty BC patients were recruited. In-silico analysis was performed. MDA-MB-231 cells were cultured and transfected with miR-17-5p oligonucleotides, MALAT1 and H19 siRNAs. Total RNA was extracted and quantified by qRT-PCR. Cellular viability, Colony forming ability and cellular migration were measured using MTT, colony forming assay and scratch assay respectively.ResultsmiR-17-5p was down-regulated while MALAT1, H19 and TNF-α were markedly upregulated in TNBC patients. In-silico analysis showed that miR-17-5p binds to MALAT1, H19 and TNF-α. Ectopic expression of miR-17-5p resulted in a significant reduction in H19, MALAT1 and TNF-α. Reciprocally, knocking down of MALAT1 or H19 resulted in a marked induction in miR-17-5p levels. However, MALAT1 and H19 siRNAs decreased TNF-α levels. Functionally, miR-17-5p resulted in a marked reduction in cellular viability, colony forming ability and cellular migration of TNBC cells.ConclusionmiR-17-5p/MALAT-1/H19/TNF-α represents an immunomodulatory loop that diverts the host immunity in favour of anti-tumour response.Legal entity responsible for the studyGerman University in Cairo.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.

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128TiP VCN-01 plus durvalumab in subjects with recurrent/metastatic head & neck squamous cell carcinoma (R/M HNSCC): Phase I clinical trial

AbstractBackgroundVCN-01 is an oncolytic adenovirus with replication restricted to cells with a nonfunctional retinoblastoma pathway. Upon selective replication VCN-01 expresses the matrix remodeling-enzyme hyaluronidase to enhance virus spreading and tumor uptake of different therapeutics, including immune check-point inhibitors. In a phase I performed in pancreatic carcinoma VCN-01 reached tumors after systemic administration and induced CD8-infiltration, tumor inflammation and PD-1/PD-L1 up-regulation. We hypothesize these intratumor effects may help to overcome the observed resistance to Durvalumab and other PD-(L)-1 checkpoint inhibitorsTrial DesignNCT03799744 is a multi-center, open-label dose-escalation phase I study evaluating the safety, tolerability and efficacy of the combination of VCN-01 plus durvalumab in R/M HNSCC patients who have progressed on prior PD-(L)-1 checkpoint inhibitors. Patients need to have neutralizing antibodies levels against adenovirus ≤1/350 dilution to be included. The study follows a 3 + 3 design with two dose levels for VCN-01 (3,3.1012 & 1.1013 vp) combined with Durvalumab at a fixed dose of 1500mg intravenous (i.v.). Two treatment arms are explored: I) Concomitant single i.v. dose of VCN-01 with durvalumab on cycle 1 day 1 followed by durvalumab Q4W; II) Sequential single i.v. VCN-01 on cycle 1 day -14 plus durvalumab on cycle 1 day 1 followed by durvalumab Q4W. Patients continue durvalumab Q4W until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to evaluate the safety and tolerability of VCN-01 with durvalumab in the two regimens of administration and to establish the recommended phase II dose. Secondary objectives are progression free survival, overall response rate by irRECIST /RECIST, VCN-01 pharmacokinetics and shedding in blood. Other exploratory biomarkers will be analyzed in tumor biopsies (immune markers), serum (hyaluronidase levels), stool (microbiome) and imaging (dynamic contrast-enhanced MRI, diffusion weighted imaging and T2 mapping). The study opened recruitment in April 2019 with 7 out of 18 planned patients enrolled at time of submission.Clinical trial identificationNCT03799744.Legal entity responsible for the studyCatalan Institute of Oncology (ICO).FundingVCN Biosciences, AstraZeneca.DisclosureM. Jove: Advisory / Consultancy: Boehringer Ingelheim. I. Braña: Advisory / Consultancy, Research grant / Funding (self): Orion Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Gliknik; Research grant / Funding (self): GSK; Research grant / Funding (self): Janssen; Research grant / Funding (self): KURA; Research grant / Funding (self): MSD; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Shattuck; Research grant / Funding (self): Northern Biologics; Research grant / Funding (self): Rakutan Aspirian; Research grant / Funding (self): Naobiotics. M. Taberna: Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Merck; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Nanobiotics. E. Garralda: Leadership role, Research grant / Funding (institution): Novartis; Leadership role: Principia Biopharma Inc; Leadership role: Lilly, S.A; Advisory / Consultancy, Leadership role: Roche / Genentech Inc; Leadership role: Loxo Oncology Inc; Advisory / Consultancy, Leadership role: F.Hoffmann La Roche Ltd; Leadership role: Symphogen A/S; Speaker Bureau / Expert testimony, Leadership role, Travel / Accommodation / Expenses: MSD; Leadership role: Incyte; Leadership role: Pharma Mar; Leadership role: Kura Oncology; Leadership role: Macrogenics; Leadership role, Travel / Accommodation / Expenses: Glycotope; Leadership role: Pierre Fabre; Leadership role: Cellestia Biotech; Leadership role, Travel / Accommodation / Expenses: Menarini Ricerche; Leadership role: Blueprint Medicines; Leadership role: Beigene; Leadership role: Sierra Oncology; Leadership role: Genmab; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services ; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: NeoMed Therapeutics; Advisory / Consultancy: SeaGen; Speaker Bureau / Expert testimony: ThermoFisher. G. Capella: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo Piqueras: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. All other authors have declared no conflicts of interest.

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125P Response assessment of metastatic uveal melanoma treated with rose bengal disodium

AbstractBackgroundRose bengal disodium (PV-10) is a small molecule oncolytic immunotherapy in clinical development for treatment of solid tumors. Upon intralesional injection, it can produce immunogenic cell death and a T-cell mediated immune response against treatment-refractory and immunologically-cold tumors.MethodsPV-10-LC-01 (NCT00986661) is an open-label phase I basket study evaluating safety, tolerability and preliminary efficacy of PV-10 in patients (pts) with solid tumors metastatic to liver. PV-10 is administered percutaneously to 1 or more hepatic tumors 1.0-4.9 cm in diameter with response assessment via contrast-enhanced CT, MRI and/or FDG PET at Day 28 then q12w. Pts with multiple injectable tumors may receive further PV-10 after Day 28. Eligible pts can receive concomitant standard care checkpoint blockade immunotherapy. In a single-center cohort of uveal melanoma pts we compared overall response and progression-free survival (PFS) using 2-dimensional European Association for the Study of Liver (2D-EASL) criteria and criteria that consider lesions outside of the liver (RECIST 1.1, irRC, irRECIST and iRECIST).ResultsEight pts who received at least 1 injection of PV-10 and had baseline and follow-up imaging were assessed: 5 received 2 doses and 3 received 1 dose. There was a difference in overall response by RECIST vs. the other criteria in 4 pts: these pts developed progression on RECIST but remained stable by 2D-EASL, irRC, irRECIST and iRECIST with disparate PFS of 91 days (RECIST) vs. 145 days. Progression by RECIST was based on appearance of new lesions for 3 pts and increase in target lesion size in 1 pt; in 1 pt the injected lesion demonstrated complete response based on 2D-EASL obtained after progression as determined by RECIST. For the remaining pts, overall response of stable disease was concordant between all response criteria; 2D-EASL demonstrated sustained partial response in injected lesions in 2 of these pts.ConclusionImaging response assessment of pts treated with PV-10 using RECIST may lead to premature and inaccurate determination of progression. 2D-EASL provides information specific to the behavior of injected lesions. Immunotherapy-centric criteria (irRC, irRECIST and iRECIST) could be a useful alternative to 2D-EASL.Clinical trial identificationNCT00986661.Legal entity responsible for the studyProvectus Biopharmaceuticals.FundingProvectus Biopharmaceuticals.DisclosureE.A. Wachter: Full / Part-time employment: Provectus Biopharmaceuticals. All other authors have declared no conflicts of interest.

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136P Profiling the tumour immune microenvironment in pleomorphic dermal sarcomas suggests its potential effectiveness for immunotherapy

AbstractBackgroundImmune-checkpoint inhibitors have shown high objective response rates and long-lasting clinical benefits in several studies, thus revolutionized cancer treatment. Pleomorphic dermal sarcoma (PDS) is a rare cutaneous tumour with local recurrences and distant metastases occurring up to 20% of the cases. With only limited treatment options in advanced stages, there is a strong rationale to explore novel treatments in PDS. In order to achieve this, the profiling of the immune environment in PDS needs to be first explored.MethodsWe collected 14 PDS cases that underwent primary surgical resection at University Hospital Cologne. With formalin-fixed paraffin-embedded (FFPE) materials, we performed a comprehensive immune-phenotype analysis using immunohistochemistry and multiplex gene expression analysis, as well as quantitative assessment of immune cells through quantitative image-analysis. Based on these findings and our preliminary studies, two patients with advanced PDS were enrolled in programmed cell death protein 1 (PD-1) inhibitor therapy.ResultsEight out of fourteen PDS cases (57%) showed abundance of CD8-positive T-lymphocyte infiltration. Three cases that had above median level of infiltration (hereinafter referred to as CD8-high) displayed high expression levels of immune-related cytokines, immunotherapy response markers, MHC-I expression, and infiltration by PD-L1-, PD-1- and LAG-3-expressing immune cells. The multivariate analysis revealed that CD8-high group highly expressed CD74, LYZ and HLA-B while the CD8-low cases overexpressed CXCL14. In addition, M2 tumor-associated macrophages (TAMs) were localized at the tumor invasion front. Likewise, both patients showed good response to anti-PD-1 therapy in combination with or without radiotherapy and remain in complete remission until now.ConclusionWe provide the initial comprehensive immune-phenotype profiling of PDS and two representative cases that were successfully treated with immune-checkpoint inhibitor for the first time. These results will aid in further assessment of PDS cases and formulate the qualification criteria for immunotherapy in individuals presenting this rare skin malignancy.Legal entity responsible for the studyUniversity Hospital Cologne.FundingEFRE 2018 (ImmunePredict).DisclosureAll authors have declared no conflicts of interest.

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132P Correlation between tumour infiltration lymphocyte and PDL-1 expression in laryngeal cancer and its prognostic significance: A prospective, non-interventional trial

AbstractBackgroundImmune system plays an important role in cancer evolution. However, cancer cells affect the immune system and use it for its growth and survival. Tumour infiltration lymphocytes and PDL-1 expression proved to play an important prognostic role in different malignancies. We aimed at evaluating this role in laryngeal cancer.MethodsWe prospectively analyzed the pre-treatment paraffin blocks for laryngeal cancer patients, whether on the laryngoscopy or operative specimens, to identify the CD8-positive cells in the tumour epithelium or stroma and the PDL-1 expression on the tumour cells. Appropriate tissue was used as positive control; placenta for PDL-1 and tonsil for CD8. A total score formed of the sum of percentage and intensity of PDL-1. A final comprehensive rate was considered as low expression when combined percentage and intensity score from 0 to 4, and high expression when score from 5-7. According to the distribution, the CD8+T cell invasion was divided into strong infiltration (> 10/100 of epithelial cells; >20/100 stromal cell infiltration) and weak infiltration (< 10/100 epithelial cells; < 20/100 stromal cell infiltration).Results40 patients were included in our study; 12 patients had early stage disease (I or II) and 28 with advanced stage (III or IV). PDL-1 expression was positive in 92.5%. Neither the PDL-1 nor CD-8 were found significantly correlated to OS in the whole population, however patients with advanced stage, median OS was significantly low for negative or low compared to high PDL-1 expression (11.7 vs 25.2 months (p = 0.036)), a trend of better OS in high CD8 Epithelial expression (25.1 versus 15.9, P = 0.514) and again trend of higher OS in high CD8 Stromal expression (25.3 versus 15.6 months, p = 0.375). Also there were significant correlation between the CD8 expression in the tumour epithelium and stroma with the PDL-1 expression with p-value of 0.001 and < 0.0001 respectively.ConclusionThere is a positive correlation between tumour infiltration lymphocytes and PDL-1 expression in laryngeal squamous carcinoma and the higher PDL-1 expression in advanced stage laryngeal cancer is associated with better OS.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.

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LBA1 Clinical efficacy of atezolizumab (atezo) in biomarker subgroups by SP142, SP263 and 22C3 PD-L1 immunohistochemistry (IHC) assays and by blood tumour mutational burden (bTMB): Results from the IMpower110 study

AbstractBackgroundThe phase III IMpower110 study (NCT02409342) is evaluating atezo (anti–PD-L1) monotherapy as 1L treatment (tx) in PD-L1–selected patients (pts) with NSCLC independent of tumour histology. IMpower110 met its primary endpoint with significant OS improvement in PD-L1–high (TC3 or IC3; ≥ 50% tumour cell [TC] or ≥ 10% tumour-infiltrating immune cell [IC]; VENTANA SP142 IHC assay) wild-type (WT; EGFR/ALK-negative) pts (HR, 0.59 [95% CI: 0.40, 0.89]; P = 0.0106). Efficacy analyses in prespecified biomarker subgroups by the SP263 and 22C3 PD-L1 IHC assays and bTMB are reported.MethodsIMpower110 enrolled 572 chemo-naive pts with stage IV NSCLC, PD-L1 ≥ 1% TC or IC (TC1/2/3 or IC1/2/3; SP142), measurable disease by RECIST 1.1 and ECOG PS 0-1. Pts were randomised 1:1 to receive atezo 1200 mg IV q3w or platinum-based chemo (4 or 6 21-day cycles). OS (primary endpoint) was tested hierarchically in WT pts. Additional analyses included OS and PFS in the SP263 and 22C3 PD-L1 IHC and bTMB populations. PD-L1 cutoffs of ≥ 1% and ≥ 50% tumour proportion score (TPS) for 22C3 and ≥ 1% and ≥ 50% TC for SP263 were evaluated; bTMB cutoffs were ≥10, ≥ 16 and ≥ 20.ResultsBiomarker-evaluable populations (BEP) in the TC1/2/3 or IC1/2/3 WT population (SP142; 554) included 534 (22C3), 546 (SP263) and 389 (bTMB) pts. Baseline characteristics in the IHC and bTMB BEP subgroups were generally balanced. OS and PFS in the PD-L1–high (TC3 or IC3; ≥ 50% TPS; ≥ 50% TC) subgroups favoured atezo (OS data shown in the table). Stepwise OS and PFS improvement, favouring atezo, was seen up to bTMB ≥ 16; no further benefit was seen at ≥ 20.ConclusionPt subgroups defined as PD-L1–high by all 3 IHC assays (SP142, 22C3, SP263) had similar OS and PFS benefit with atezo, despite the different assay sensitivities and scoring algorithms. Enrichment in clinical benefit, favouring atezo, was also seen in bTMB positive subgroups. Atezo monotherapy is a potential new 1L tx option for pts with PD-L1–high NSCLC. Table: LBA1SubgroupMedian OSHRaa (95% CI)AtezoChemonmonmoVENTANA SP142 (n = 554)TC1/2/3 or IC1/2/3 WT27717.527714.10.83(0.65, 1.07)TC3 or IC3 WT10720.29813.10.59(0.40, 0.89)Dako 22C3 (n = 534)22C3 BEP26817.526614.10.82(0.64, 1.06)≥ 50% TPS13420.212611.00.60(0.42, 0.86)≥ 1% TPS21317.820114.00.73(0.55, 0.97)VENTANA SP263 (n = 546)SP263 BEP27117.227514.90.85(0.66, 1.09)≥ 50% TC15019.514316.10.71(0.50, 1.00)≥ 1% TC21217.821014.00.77(0.58, 1.02)Foundation Medicine bTMB (n = 389)bTMB BEP19613.319315.30.98(0.74, 1.30)≥ 109211.28310.30.87(0.58, 1.30)≥ 164213.9458.50.75(0.41, 1.35)≥ 202717.22910.50.77(0.36, 1.64)aStratified OS HRs for SP142 only.Clinical trial identificationNCT02409342.Editorial acknowledgementMedical writing assistance for this abstract was provided by Kia C. E. Walcott, PhD, of Health Interactions, and funded by F. Hoffmann-La Roche, Ltd.Legal entity responsible for the studyF. Hoffmann-La Roche.FundingF. Hoffmann-La Roche.DisclosureR.S. Herbst: Advisory / Consultancy: Abbvie Pharmaceuticals; Advisory / Consultancy: ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bristol‐Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: EMD Serrano; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy: Heat Biologics; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy, Research grant / Funding (institution): Merck and Company; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer, Sanofi, Seattle Genetics, Nektar; Advisory / Consultancy: Shire PLC, Spectrum Pharmaceuticals, Symphogen, Tocagen, Tesaro ; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Infinity Pharmaceuticals; Advisory / Consultancy: NextCure; Advisory / Consultancy: Junshi Pharmaceuticals. F. de Marinis: Research grant / Funding (self): F. Hoffmann-La Roche. G. Giaccone: Research grant / Funding (self): F. Hoffmann-La Roche. N. Reinmuth: Research grant / Funding (self): F. Hoffmann-La Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer-Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda. A. Vergnenegre: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: F. Hoffmann-La Roche. C.H. Barrios: Research grant / Funding (self): Abbvie; Research grant / Funding (self): Amgen; Research grant / Funding (self): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Celgene; Research grant / Funding (self): Covance; Research grant / Funding (self): Lilly; Research grant / Funding (self): Medivation; Research grant / Funding (self): Merck Serono; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp Dohme (MSD) ; Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Research grant / Funding (self): PharmaMar; Advisory / Consultancy, Research grant / Funding (self): Roche/Genentech; Research grant / Funding (self): CPO; Research grant / Funding (self): PUCRS; Research grant / Funding (self): LACOG; Research grant / Funding (self): GBECAM; Research grant / Funding (self): INCA-Brazil; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: GSK; Advisory / Consultancy: EIsai; Advisory / Consultancy: Bayer. M. Morise: Research grant / Funding (self): F. Hoffmann-La Roche; Honoraria (self), Lecture fee: Eli Lilly; Honoraria (self), Research grant / Funding (self), Lecture fee, Principal investigator of contact clinical trial: Chugai; Honoraria (self), Research grant / Funding (self), Lecture fee. Principal investigator of contact clinical trial: Astra Zeneca; Honoraria (self), Lecture fee: Ono; Honoraria (self), Research grant / Funding (self), Lecture fee, Principal investigator of contact clinical trial: Pfizer; Honoraria (self), Lecture fee: MSD; Research grant / Funding (self), Principal investigator of contact clinical trial: Merk serono; Research grant / Funding (self), Principal investigator of contact clinical trial: Kissei; Research grant / Funding (self), Principal investigator of contact clinical trial: Taiho; Research grant / Funding (self), Principal investigator of contact clinical trial: Novartis; Research grant / Funding (self): Boehringer-ingelheim. E. Felip: Research grant / Funding (self): F. Hoffmann-La Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Abbvie; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astra Zeneca; Advisory / Consultancy: Bergenbio; Advisory / Consultancy: Blue Print Medicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Medscape; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck KgaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Prime Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Samsung; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: Touchtime. Z. Andric: Research grant / Funding (self): F. Hoffmann-La Roche. S. Geater: Research grant / Funding (self): F. Hoffmann-La Roche. M. Ozguroglu: Research grant / Funding (self): F. Hoffmann-La Roche.S. Mocci: Full / Part-time employment: Genentech, Inc. M. McCleland: Full / Part-time employment: Genentech, Inc.. W. Zou: Full / Part-time employment: Genentech, Inc.. I. Enquist: Full / Part-time employment: Genentech, Inc.. K. Komatsubara: Full / Part-time employment: Genentech, Inc.. Y. Deng: Full / Part-time employment: Genentech, Inc.. H. Kuriki: Full / Part-time employment: Genentech, Inc.. D.R. Spigel: Research grant / Funding (institution): F. Hoffmann-La Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genetech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Moderna Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: TRM Oncology; Advisory / Consultancy: Precision Oncology; Advisory / Consultancy: Evelo Therapeutics; Advisory / Consultancy: Illumina; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): University of Texas Southwestern Medical Center- Simmons Cancer Center; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): Oncogenex; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): GRAIL; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Aeglea Biotherapeutics; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): Millennium; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. J. Jassem: Research grant / Funding (self): F. Hoffmann-La Roche; Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astra Zeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche.

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112P Identification of a novel promiscuous anti-NY-ESO-1 immunogenic CD4+ peptide containing a CD8+ T-cell epitope highly present in metastatic gastric cancer responding to combined radiotherapy/anti-PD-1 immunotherapy

AbstractBackgroundImmune checkpoint inhibitors offer the prospect of long term disease control in solid tumor types. NY-ESO-1 is a cancer-testis antigen expressed by 20% of advanced gastric cancers, known to induce humoral and cellular immune responses. Combination of anti-PD-1 with radiotherapy is currently investigated. Radiotherapy has the ability to promote immunogenic cell death leading to the release of tumor antigens, increasing infiltration and activation of T cells. In this study, we investigated the immune response to the NY-ESO-1 antigen in metastatic gastric cancer treated with anti-PD-1 (pembrolizumab).MethodsT cells response to the NY-ESO-1 antigen was investigated by ELISPOT against NY-ESO-1 PepMix, against the 43 single peptides overlapping the NY-ESO-1 whole protein and the NY-ESO-1 HLA-A2 restricted peptide. The IEDB1 prediction database was used to predict the patient’s HLA DR, DQ and DP binding to NY-ESO-1. We subsequently characterized the phenotypic and functional activity of the patient T cells using flow cytometry analysis.ResultsWe have identified a novel promiscuous immunogenic NY-ESO-1 peptide restricted to the 4 HLA-DQ and HLA-DP alleles and containing the known NY-ESO-1 HLA-A2-02:01 (P157-165) immunogenic epitope. CD8+ T cells were increased during combined therapy and at disease resolution in which its PD-1+CD8+ subset was increased during combined therapy and resolution then decreased at disease progression. The CD107+ cytotoxic subset of the CD8+/HLA-A2-NY-ESO-1-dextramer+ T cells was markedly increased during combined therapy and at resolution then dramatically decreased at re-progression.ConclusionWe have identified a novel promiscuous anti-NY-ESO-1 immunogenic CD4+ peptide containing the P157-165 HLA-A*02:01/CD8+ epitope that was highly presented at disease resolution and decreased at progression after combined radiotherapy/anti-PD-1 immunotherapy. Our study showed that radiation therapy combined with immune checkpoint blockade would enhance the immune response that correlates with the patient clinical outcome.Legal entity responsible for the studyHamad Medical Corporation.FundingHamad Medical Corporation.DisclosureAll authors have declared no conflicts of interest.

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106P A single dose of local IL-12 promotes anti-tumor effect of anti-EGFRvIII-CAR-T cells in a syngeneic murine model of glioblastoma

AbstractBackgroundGlioblastoma multiforme (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Immunotherapy with chimeric antigen receptor (CAR) T cells is gaining attention as a promising strategy to treat this disease. An ideal candidate to target with CAR T cells is the tumor specific variant III of the epidermal growth factor receptor (EGFRvIII), which represents a mutation found in more than 30% of glioblastoma patients. However, anti-EGFRvIII-CAR modified T cell therapy has shown only limited effects in GBM patients, in all likelihood due to the immunosuppressive microenvironment that CAR T cells encounter in the tumor microenvironment (TME) of gliomas. To make gliomas susceptible to CAR T cell therapy, combinatorial approaches to convert the TME are required.MethodsMice received 5Gy TBI on day 15 post implantation, followed by intra-tumoral injection of IL-12:Fc on day 20 and infusion of EGFRvIII-directed CAR or non-transduced T cells on day 21. To perform functional analysis, we adopted high-parametric flow-cytometric characterization of the TME using 23 independent parameters 8 days after CAR T cells injection. We utilized unsupervised validated clustering approaches (FlowSOM and CellCNN) to discriminate between different cell populations.ResultsHere, we demonstrate that the combination of a single dose of local IL-12 with anti-EGFRvIII-CAR T cells synergizes to increase long-term survival in a syngeneic mouse model of GBM. IL-12 not only boosted the pro-inflammatory and cytotoxic activity of anti-EGFRvIII-CAR T cells, but also induced a complete remodelling of the tumor microenvironment (TME) with strong endogenous anti-tumor immune T cell responses. These findings highlight the capacity of IL-12 to induce an immunologically “cold” tumor such as GMB to acquire responsiveness to CAR T cells therapy.ConclusionThis study demonstrates the capacity of IL-12 as local “adjuvant” therapy to boost the efficacy of CAR T cells and to awake the endogenous anti-tumor T cell responses.Legal entity responsible for the studyUniversity of Zurich.FundingUniversity Research Priority Project and Advanced T-cell Engineered for Cancer Therapy.DisclosureM. Pule: Honoraria (self), Honoraria (institution): Autolus LTD. All other authors have declared no conflicts of interest.

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102P Results from a phase II trial of pembrolizumab (P) plus gemcitabine (Gem) in patients (pts) with HER2-negative advanced breast cancer (ABC): GEICAM/2015-04 (PANGEA-Breast) study

AbstractBackgroundThis trial is based on a combination strategy with two immunostimulatory agents in the search of synergism that may induce responses with long-term clinical benefit in ABC pts. Safety data from the run-in-phase were published in ESMO IO 2018. Here, we report the results from the phase II part of the study.MethodsHER2-negative ABC pts previously treated with anthracyclines and taxanes (unless contraindicated), ≤ 4 chemotherapy lines and/or ≥ 2 hormone therapy lines, and irrespective of PD-L1 status, were eligible. Study treatment consisted of 21-day cycles (cy) of P 200mg on day 1 and Gem 1250mg/m2 on days 1 and 8 until progressive disease (PD) or unacceptable toxicity, whatever occurred first. Primary objective was Objective Response Rate (ORR).ResultsThirty-six pts were included in the first stage of a Simon’s design. Recruitment was stopped as only 5 pts presented an objective response (partial) (≥ 7 responses needed to continue recruiting pts). Median age was 52 years (range 31-77), 21 pts had triple negative disease, the majority of pts had an ECOG performance status ≤ 1 (n = 35), visceral involvement (n = 28) and ≥ 2 metastatic locations (n = 27). Median number of prior lines (any therapy) for ABC was 4 (range 0-11). Pts received a median of 4.5 cy of Gem and 4 cy of P (same range for both drugs, 1-24). The median relative dose intensity of P and Gem was 100% and 80%, respectively. Treatment discontinuation due to PD was reported on 29 pts. The ORR was 15.2% (95% confidence interval (CI) 5.1-31.9) and the Clinical Benefit Rate was 17% (95% CI 33.5-69.2); median duration of objective response was 4.3 months (mo) (95% CI 2.3-7.4), median Progression-Free Survival was 3.1 mo (95% CI, 2-4.3), and median Overall Survival was 7.9 mo (95% CI 6.5-10.3). Eight pts were on treatment ≥ 6 mo before PD (2 pts on 11.4 and 16.1 mo). Grade (G) ≥ 3 AEs related to the study treatment were reported on 14 pts (39%), being neutropenia the most common G3 (22.2%) and G4 (5.6%) AE.ConclusionP can be safely combined with Gem, the combination did not meet the efficacy objective in terms of ORR but 22.2% pts were on treatment ≥ 6 mo.Clinical trial identificationNCT03025880.Legal entity responsible for the studyGEICAM Spanish Breast Cancer Group.FundingMSD.DisclosureJ. Cruz: Honoraria (self), Advisory / Consultancy: Glaxo; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. M. Ramos Vazquez: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. J. Cortés: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Celgene; Advisory / Consultancy: Cellestia; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biothera Pharmaceutical; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Advisory / Consultancy: Polyphor; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Advisory / Consultancy: GSK; Honoraria (self): Novartis; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (institution), MedSIR (Stock, patent and intellectual property): Ariad Pharmaceuticals. Baxalta GMBH/Servier Affaires. Bayer Healthcare. Guardanth Health. Piqur Therapeutics. Puma C. Queen Mary University of London. Seagen. All other authors have declared no conflicts of interest.

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97P Impact of prior lines of systemic therapy (PST) on the efficacy of cemiplimab, a human monoclonal anti–PD-1, in patients (pts) with advanced cutaneous squamous cell carcinoma (CSCC)

AbstractBackgroundCemiplimab demonstrated antitumour activity and an acceptable safety profile in a phase II study of pts with CSCC (NCT02760498). Here, we report efficacy by PST.MethodsThe primary objective of the study is to evaluate the objective response rate (ORR) by independent central review (ICR). Pts with metastatic CSCC (mCSCC; Group 1) and locally advanced CSCC (Group 2) received 3 mg/kg Q2W for 96 weeks, and mCSCC received 350 mg Q3W for 54 weeks (Group 3). Data cutoff dates were 20 September 2018 (Groups 1 and 3) and 10 October 2018 (Group 2).ResultsOf the 193 pts enrolled, 128 had cemiplimab as first-line therapy (1LT) and 65 had PST (table). Median follow-up was 9.4 months. The ORR per ICR was 46.9% (95% CI: 38.0–55.9; 17 complete responses [CR] and 43 partial responses [PR]) in pts with cemiplimab as 1LT and 38.5% (95% CI: 26.7–51.4; five CRs and 20 PRs) in pts with PST. The disease control rate per ICR was 75.8% (95% CI: 67.4–82.9) in pts with cemiplimab as 1LT and 64.6% (95% CI: 51.8–76.1) in pts with PST. Estimated 12-month duration of response (DOR) was 88.3% (95% CI: 73.9–95.0) among all 60-responding pts with cemiplimab as 1LT and 90.9% (95% CI: 68.1–97.6) among all 25-responding pts with PST. Estimated Kaplan–Meier 12-month progression-free survival was 56.9% (95% CI: 46.4–66.2) in pts with cemiplimab as 1LT and 46.7% (95% CI: 33.4–58.9) in pts with PST. 12-month overall survival was 90.7% (95% CI: 83.7–94.8) in pts with cemiplimab as 1LT and 76.3% (95% CI: 63.7–85.0) in pts with PST. The most common treatment-related adverse events in all pts were fatigue (n = 37, 19.2%), pruritus (n = 25, 13.0%) and diarrhoea (n = 24, 12.4%) and rash and maculopapular rash (both n = 21, 10.9%).ConclusionAs demonstrated by the numerically higher ORR, 12-month PFS, and OS, the efficacy of cemiplimab in advanced CSCC may be greater when used as 1LT, supporting its early use for patients with advanced CSCC. Table: 97P Therapeutic setting, number of regimens and type of systemic therapies in pts with PSTPts with PST (N = 65)Therapeutic setting, n (%)Metastatic disease22 (33.8)Adjuvant10 (15.4)Neoadjuvant4 (6.2)Chemotherapy with concurrent radiation35 (53.8)Other8 (12.3)Number of regimens at baseline, median (range)1 (1–4)Type of PST, n (%)Antineoplastic agents65 (100.0)Platinum compounds46 (70.8)Monoclonal antibodies18 (27.7)Pyrimidine analogues15 (23.1)Taxanes15 (23.1)Protein kinase inhibitors4 (6.2)Combinations of antineoplastic agents3 (4.6)Folic acid analogues1 (1.5)Other antineoplastic agents1 (1.5)Corticosteroids for systemic use1 (1.5)Glucocorticoids1 (1.5)Clinical trial identificationNCT02760498.Editorial acknowledgementMedical writing support under the direction of the authors was provided by Kate Carolan, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc. and Sanofi according to Good Publication Practice guidelines.Legal entity responsible for the studyRegeneron Pharmaceutical, Inc. and Sanofi.FundingRegeneron Pharmaceutical, Inc. and Sanofi.DisclosureD. Rischin: Research grant / Funding (institution), Non-remunerated activity/ies: Regeneron Pharmaceuticals, Inc.; Research grant / Funding (institution): Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme; Research grant / Funding (institution), Non-remunerated activity/ies: Bristol-Myers Squibb; Research grant / Funding (institution), Non-remunerated activity/ies: GSK. N.I. Khushalani: Advisory / Consultancy, Research grant / Funding (self): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): HUYA Bioscience International; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy, Data safety monitoring committee: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: ARRAY Biopharma; Advisory / Consultancy: Immunocore; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Cellgene; Research grant / Funding (self): Amgen; Honoraria (self): Sanofi; Shareholder / Stockholder / Stock options: Bellicum Pharmaceuticals; Shareholder / Stockholder / Stock options: Mazor Robotics; Shareholder / Stockholder / Stock options: Amarin; Shareholder / Stockholder / Stock options: Transenetrix. C.D. Schmults: Advisory / Consultancy, Research grant / Funding (self), Steering committee member: Castle Biosciences; Advisory / Consultancy, Research grant / Funding (self), Steering committee member: Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Sanofi; Research grant / Funding (self): Novartis; Research grant / Funding (self): Genentech; Research grant / Funding (self): Merck; Advisory / Consultancy, Chair for NCCN: NCCN. A. Guminski: Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Sun Pharma; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy: Eisai; Advisory / Consultancy: Pfizer; Non-remunerated activity/ies: Astellas; Research grant / Funding (institution), Clinical trial unit support: PPD Australia. A.L.S. Chang: Advisory / Consultancy, Research grant / Funding (self): Regeneron Pharmaceuticals, Inc.; Research grant / Funding (self): Novartis; Research grant / Funding (self): Galderma; Advisory / Consultancy, Research grant / Funding (self): Merck. K.D. Lewis: Research grant / Funding (self), Grants and personal fees: Regeneron Pharmaceuticals, Inc.. A.M. Lim: Non-remunerated activity/ies: Merck Sharp & Dohme; Travel / Accommodation / Expenses: Bristol-Myers Squibb. L. Hernandez-Aya: Advisory / Consultancy: Massive Bio; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Regeneron Pharmaceuticals, Inc.; Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (self): Immunocore; Research grant / Funding (self): Merck Sharp & Dohme; Research grant / Funding (self): Polynoma; Research grant / Funding (self): Corvus Pharmaceuticals; Research grant / Funding (self): Roche; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Amgen; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Takeda. B.G.M. Hughes: Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Research grant / Funding (institution): Amgen. D. Schadendorf: Research grant / Funding (institution): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Amgen; Advisory / Consultancy: Leo Pharma; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Merck-EMD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Incyte; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution), Patients’ fees: MSD; Advisory / Consultancy, Steering committee honorarium: 4SC; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array; Advisory / Consultancy, Research grant / Funding (institution), Patients’ fees: Philiogen. A. Hauschild: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD/Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Provectus; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Philogen; Advisory / Consultancy, Research grant / Funding (institution): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: OncoSec. E. Stankevich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. J. Booth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. S. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. Z. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. J. Desai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. I. Lowy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. M.G. Fury: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. M.R. Migden: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Regeneron Pharmaceuticals, Inc.; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Travel / Accommodation / Expenses: Sun Pharma.

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