Immunotherapy of cancer

Transcription

1 Immunotherapy of cancer Chair(s) Session Type Details S. Scholl (Paris, France)T. B. Powles (London, United Kingdom) Poster Discussion session ESMO 2016 Congress, , 09:30-10:30, Berlin 1049PD - A phase 1b study (SCORES) assessing safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of durvalumab combined with AZD9150 or AZD5069 in patients with advanced solid malignancies and SCCHN D. Hong (Houston, United States of America)G. Falchook (Denver, United States of America) C. E. Cook (Waltham, United States of America)W. Harb (Lafayette, United States of America) P. Lyne (Waltham, United States of America)P. McCoon (Waltham, United States of America) M. Mehta (Waltham, United States of America)P. Mitchell (Waltham, United States of America) G. M. Mugundu (Waltham, United States of America)M. Scott (Waltham, United States of America) J. S. Wang (Sarasota, United States of America) Activating the immune system for therapeutic benefit in cancer has long been a goal in immunooncology. Combining a PD-L1 antagonist, durvalumab (D), with novel agents targeting immunosuppression in the tumor bed such as AZD9150 (A9, an antisense oligonucleotide against STAT3) or AZD5069 (A5, a CXCR2 antagonist) may strongly enhance anti-tumor responses. Patients (pts) with advanced solid malignancies (N = 31) were enrolled using a CRM based approach to identify dose combinations of A9 + D and A5 + D with an incidence of dose-limiting toxicities (DLT) less than 33%. Up to 6 evaluable pts per cohort were initially assessed. For all, D was fixed at 20 mg/kg Q4W with A9 at dose levels (DL) of (1) 2mg/kg QW or (2) 3mg/kg QW i.v; A5 was started at DL1 40 mg po bid, then DL2 80 mg bid. The primary objective was to determine the MTD and recommended phase II dose (RP2D), and secondarily safety, PK, pharmacodynamics, biological and clinical activity for each combination. In the A9 + D arm, 11 pts (DL1 = 4, DL2 = 7) were treated. The most common drug related adverse events (AEs) were thrombocytopenia (64%), neutropenia (45%) and ALT/AST increase (36%) with no DLTs or drug-related Gr 4 events. The MTD/RP2D for AZD9150 was 3 mg/kg QW. In the A5 + D arm, 20 pts were enrolled (DL1 = 9; DL2 = 11) with most common drug related AEs of neutropenia (35%), fatigue or anorexia (20%). One DLT of Gr 3 neutropenia occurred at 40 mg bid; 2 similar DLTs were noted at DL2. The MTD/RP2D for AZD5069 was 40 mg po bid. Two pts in the A9 + D arm achieved a confirmed PR (MSH2/6 mutant mcrpc, GE jxn tumor) per modified irecist. Three more pts on A9 + D (laryngeal, colorectal, leiomyosarcoma) and two on A5 + D (breast, urothelium) demonstrated stable disease; the last pt's course was clearly consistent with pseudoprogression. Target engagement was shown in peripheral blood of A9 + D (STAT3 knockdown) and A5 + D (CXCR2-elicited cytokines) pts.

2 Combinations of durvalumab with AZD9150 or AZD5069 have a manageable toxicity profile and encouraging evidence of activity. Enrollment into phase 2 SCCHN expansion cohorts continues. Pharmacokinetic and pharmacodynamic data will be presented. NCT AstraZeneca Pharmaceuticals LP AstraZeneca Pharmaceuticals LP D. Hong, G. Falchook, W. Harb, J.S. Wang: Research funding for clinical trials from AstraZeneca. C.E. Cook: AstraZeneca employee and stock holder. P. Lyne, P. McCoon, M. Mehta, P. Mitchell, M. Scott, G.M. Mugundu: Employee of AstraZeneca Pharmaceuticals LP. 1050PD - Combination of MEDI0680, an anti-pd-1 antibody, with durvalumab, an anti-pd-l1 antibody: A phase 1, open-label study in advanced malignancies O. Hamid (Los Angeles, United States of America)L. Q. Chow (Seattle, United States of America) R. E. Sanborn (Portland, United States of America)S. Marshall (Gaithersburg, United States of America) C. Black (Gaithersburg, United States of America)M. Gribbin (Gaithersburg, United States of America) J. McDevitt (Gaithersburg, United States of America)J. J. Karakunnel (Gaithersburg, United States of America) J. E. Gray (Tampa, United States of America) The PD-1/PD-L1 pathway is a key regulator of T-cell activation and a promising target for cancer treatment. MEDI0680 (M) is a humanized IgG4κ mab specific for human PD-1 that blocks interaction with PD-L1 and programmed cell death ligand-2 (PD-L2). Durvalumab (D; MEDI4736) is a selective, high-affinity, engineered human IgG1 mab that blocks PD-L1 binding to PD-1 and CD80. Blocking both the PD-1 receptor and its ligand by combining M + D offers the potential for complete PD-1/PD-L1 axis inhibition. This ongoing Phase 1 open-label, dose-escalation and expansion study is evaluating M + D in patients (pts) 18 years with relapsed/refractory advanced solid malignancies and ECOG performance status 0-1 (NCT ). The primary objectives are safety and maximum tolerated dose (MTD). Secondary objectives include antitumor activity. As of 2 November 2015, 30 pts across various histologies were treated in 6 dose cohorts (Table) with 50% remaining on study. 1 dose-limiting toxicity occurred (Cohort 5; Grade 3 elevated AST/ALT). The MTD has not been reached. The most common drug-related AEs were pruritus (17%); diarrhea and fatigue (both 13%); and flushing, peripheral edema, and pyrexia (each 10%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 2 pts (7%) discontinued due to drug-related AEs. Of 26 evaluable pts, 1 had a complete response (CR; Cohort 5; bladder cancer), 3 had a partial response (PR) and 9 had stable disease (SD). Increased Ki67+ (proliferating) CD4+ and CD8+ T cells and elevated circulating IFNɣ, CXCL9, CXCL10,

3 and CXCL11 levels were observed with M + D, indicating pharmacodynamic activity of PD-1/PD-L1 pathway blockade. Updated clinical data will be presented. Cohort Total Dose every 2 weeks (Q2W) (mg/kg), M + D N Patients with drug-related AEs, n (%) All grades 2 (50) 3 (60) 3 (100) 2 (67) 8 (89) 3 (50) 21 (70) Grade 3 1 (25) 0 1 (33) 0 3 (33) 0 5 (17) All grades leading to discontinuation Responses* Objective response rate (CR + PR), n/n (%) Disease control (CR + PR + SD 8 weeks), n/n (%) *Response evaluable population 1 (25) 1 (20) 1 (33) 1 (33) 2 (22) 0 6 (20) 1/4 (25) 2/4 (50) /8 (38) 1/5 (20) 1/3 (33) 0 5/8 (63) 0 4/26 (15) 0 9/26 (35) M 10 mg/kg + D 10 mg/kg Q2W appears to be well-tolerated and active in this population. NCT MedImmune MedImmune O. Hamid: Consulting/Advisory: Merck, Merck Serono, Pfizer, Amgen, Novartis, Roche, BMS, Genentech Speakers Bureau: BMS, Genentech, Novartis Research funding: None. L.Q. Chow: Honoraria: Astellas Consulting/Advisory: Novartis, Amgen, Emergent Research funding: Novartis, BMS, Eli Lilly/Imclone Advisory board; travel & accommodations/research funding: Merck. R.E. Sanborn: Consulting/Advisory: Amgen Research funding: BMS, Medimmune. S. Marshall: Employment: MedImmune, Amplimmune Stock options: MedImmune. C. Black: Employment: MedImmune Stock/ownership: AZ. M. Gribbin: Employment: Medimmune Stock ownership: MedImmune. J. McDevitt: Employment: MedImmune Stock/ownership: MedImmune (AZ). J.J. Karakunnel: Employee of MedImmune and own stock or options in AstraZeneca. JJK is also an employee of MedStar Montgomery Medical Center and Fauquier Hospital. J.E. Gray: Consulting/Advisory: AZ Travel, accommodation, expenses: AZ. LBA38 - Interim safety and clinical activity in patients with advanced NSCLC from a multi-cohort phase 1 study of ramucirumab (R) plus pembrolizumab (P)

4 R. S. Herbst (New Haven, United States of America)J. Martin-Liberal (Barcelona, Spain)E. Calvo (Madrid, Spain) N. Isambert (Dijon, France)J. C. Bendell (Nashville, United States of America)P. Cassier (Lyon, France) J. Perez-Gracia (Pamplona, Spain)J. Yang (Bridgewater, United States of America) J. Rege (Bridgewater, United States of America)G. Mi (Indianapolis, United States of America) D. Ferry (Bridgewater, United States of America)L. Paz-Ares (Seville, Spain) Hallmarks of tumor growth include angiogenesis and immunosuppression. This is the first study to combine R (VEGFR2 antibody) with P (PD-1 antibody) to target both processes simultaneously. R and P have both shown clinical activity in multiple tumor types. This ongoing phase 1a/b study (NCT ) enrolled pts with gastric or gastroesophageal junction (G/GEJ), NSCLC, urothelial carcinoma (UC), or biliary tract cancer (BTC) following progression on systemic therapy. The primary end point was to define safety and tolerability of adding R to P; preliminary efficacy will be examined. The DAKO PD-L1 22C3 IHC pharmdx assay was used to classify PD-L1 as strong pos ( 50%), weak pos (1-49%), or neg for NSCLC pts. As of data cut-off on 23-June-2016, 91 pts have been enrolled with G/GEJ, UC or NSCLC and 66 (73%) experienced a treatment-related AE (TRAE). Fifteen (16%) pts experienced grade 3-4 TRAEs, most commonly colitis (4%) and hypertension (4%). One treatment related death occurred in the G/GEJ cohort (pneumocystis pneumonia and pulmonary sepsis). Pts with previously treated advanced NSCLC (n = 27) received R at 10 mg/kg on Day 1 with P 200 mg on Day 1 q3w. The median age was 65, 78% were male, 96% had a history of smoking, 78% had adenocarcinoma and 15% had squamous-cell carcinoma. Sixteen (59%) pts received 2 and 4 (15%) pts received 3 prior treatment regimens for their disease. Overall, 22 (81%) pts experienced a TRAE, most commonly asthenia (19%) and hypertension (19%). Two (7%) pts experienced grade 3-4 TRAEs (adrenal insufficiency, hyponatremia, delirium, and infusion related reaction). Eight (30%) pts had an objective response (1 unconfirmed). Responses occurred in both histological subtypes and all PD-L1 groups. The disease control rate was 85%. Median time to response was 1.45mo and median duration of response has not been reached. Median PFS has not been reached (95% CI, 3.98 to NR). Median duration of treatment is 6.8mo or longer. Objective responses were still ongoing in all responders. R + P generated no new safety signals and demonstrated promising clinical activity in pts with previously treated advanced NSCLC, including PD-L1 neg pts. NCT Eli Lilly and Company Eli Lilly and Company

5 R.S. Herbst: funding from Merck and Lilly, and served as an advisory board member for AstraZeneca, Bristol-Myers Squibb, Genentech, Roche and Lilly. E. Calvo: Consulting-Novartis,GSK,Astellas,Roche,Lilly,Nanobiotech,Pfizer Speaker's Bureau -Novartis Research Boehringer Ingelheim,Roche,BMS,Novartis,PsiOxus,Janssen,Eisai,Abbvie, OncoMed,Pharmamar,Puma Travel, Expenses Lilly,PsiOxus,Novartis. P. Cassier: Grants/research - Roche/Genentech, Novartis, AstraZeneca, Celgene, Bayer, BluePrint, Amgen, Ignyta, Eli Lilly Co Honorarium - Roche, Novartis, Amgen. J.L. Perez-Gracia: Corporate Sponsored Research Eli Lilly and Company. J. Yang, J. Rege, G. Mi, D. Ferry: Employment and stock ownership Eli Lilly and Company. L. Paz-Ares: Scientific advice - Roche, Lilly, Astra Zeneca, Merck Sharp, Boehringer Ing.,Bristol Meyers Squibb, Pfizer, Clovis Oncology, Novartis, Bayer, Amgen. All other authors have declared no conflicts of interest. 1051PD - The MITCI (phase 1b) study: a novel immunotherapy combination of coxsackievirus A21 and ipilimumab in patients with advanced melanoma B. Curti (Portland, United States of America)J. Richards (Chicago, United States of America) M. Faries (Los Angeles, United States of America)R. H. Andtbacka (Utah, United States of America) M. Grose (Sydney, Australia)R. Karpathy (Sydney, Australia)D. Shafren (Sydney, Australia) TM CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21). In a phase 2 study, intratumoral (i.t.) CVA21 injection of advanced melanoma lesions with CVA21 resulted in increases in tumor immune-cell infiltration, up-regulation of ɣ-inf response and immune-checkpoint molecule genes, including CD122 which may be a potential prognostic factor for anti-tumor activity by anti-ctla-4 blockade strategies. Presented are the preliminary data of the open-label, Phase Ib MITCI (Melanoma Intra-Tumoral Cavatak and Ipilimumab) study of novel immunotherapy combination CVA21 and ipilimumab in patients (pts) with advanced melanoma. The Phase Ib MITCI study is investigating the efficacy and safety of i.t. CVA21 and i.v. ipilimumab in 26 pts with treated or untreated unresectable Stage IIIC-IVM1c melanoma. 8 Pts received up to 3 x 10 TCID CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then 50 q3w for a further 6 series of injections. Ipilimumab (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. The first response assessment (irwho) occurred at study Day 106. The primary endpoint was to assess safety of CVA21 in combination with ipilimumab treatment (tx). At present, of the 16 pts enrolled, no DLT's have been reported. Combination tx has been generally well-tolerated with only one Gr 3 or higher tx-related AE being ipilimumab-related fatigue. The study has met its primary statistical futility endpoint of achieving 4 confirmed objective responses (CR or PR) in the first 12 pts enrolled. Currently, of the first 7 pts eligible for investigator response assessment, ORR for the ITT population is 57.1% (4/7), with the ORR for ipilimumab-naïve pts being 67% (4/6). The

6 DCR (CR + PR + SD) on the ITT population is currently 86% (6/7). All responses were observed by 3.5 mths with complete tumor responses being observed in individual injected and non-injected lesions. Intratumoral CVA21 + ipilimumab tx of pts with advanced melanoma has been generally well tolerated. The combination immunotherapy tx has displayed anti-tumor activity in both local, visceral and non-visceral lesions in a number of patients that have failed previous lines of immunotherapy. NCT Viralytics Limited Viralytics Limited B. Curti: Honoraria: Prometheus Clinical trial support; Prometheus Bristol-Myers Squibb MedImmune. J. Richards: Stock Ownership - Bristol-Myers Squibb (I). M. Faries: Served as an advisor or consultant for: Amgen Inc.; Astellas Pharma, Inc.; Genentech, Inc. R.H.I. Andtbacka: Consulting or Advisory Role - Amgen Speakers' Bureau - Novartis Research - Amgen (Inst); Viralytics (Inst). M. Grose, R. Karpathy: Viralytics stock and employment at Viralytics. D. Shafren: stock ownership and CSO. Invited discussant abstracts 1049PD, 1050PD, 1051PD and LBA38 T. Powles Questions to discussant 1052PD - Phase 1 study of MEDI0562, a humanized OX40 agonist monoclonal antibody (mab), in adult patients (pts) with advanced solid tumors B. S. Glisson (Houston, United States of America)R. Leidner (Portland, United States of America) R. L. Ferris (Pittsburgh, United States of America)J. Powderly (Huntersville, United States of America) N. Rizvi (New York, United States of America)J. D. Norton (Gaithersburg, United States of America) J. Burton (Cambridge, United Kingdom)M. C. Lanasa (Gaithersburg, United States of America) S. P. Patel (La Jolla, United States of America) In preclinical studies, OX40 agonists have been shown to stimulate immune effector and memory T cell function while attenuating immunosuppressive function of regulatory T cells, leading to anti-tumor activity. This is a Phase 1 study evaluating MEDI0562, a humanized OX40 agonist mab, in adult pts with advanced solid tumors. The study has 2 phases: dose escalation and dose expansion. Dose escalation follows design with pts enrolled in sequential cohorts of up to 6 dose levels of MEDI0562 (0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg, via intravenous infusion). Tumor assessments are performed every 8 weeks. Selected pts have mandatory pre- and on-treatment tumor biopsies to explore the relationship between drug

7 exposure and pharmacodynamics. We report the preliminary results of safety, tumor response, pharmacokinetics, and pharmacodynamics in the dose escalation phase. As of April , 27 pts were treated (n = 7, 9, 7, 4 received 0.03, 0.1, 0.3, and 1 mg/kg MEDI0562, respectively). Adverse events (AEs) and treatment-related AEs were seen in 24 (88.9%) and 16 (59.3%) pts, respectively; the only related AE occurring in 10% of pts was fatigue (8/27, 29.6%). Most pts experienced AEs of Grade 1 and 2 in severity. Serious AEs (SAEs) were seen in 12 (44.4%) pts; no treatment-related or immune-related SAEs were observed. No related treatment discontinuations, deaths or dose limiting toxicities have occurred. Of 19 evaluable pts, 1 pt (0.03 mg/kg) with squamous cell carcinoma of the larynx had partial response at first tumor assessment and maintained for 3.7+ months (ongoing); 4 pts had stable disease. Serum exposure of MEDI0562 increased approximately dose proportionally. A 2-3-fold mean increase in peripheral Ki67+ CD4+ memory T cells was observed. Paired tumor biopsies showed induction of PD-L1 expression and increased CD8+ T cell infiltration in 2 of 3 evaluated pts, including 1 pt at 0.03 mg/kg. Updated clinical data will be presented at the meeting. Preliminary data showed that MEDI0562 is generally well tolerated in adult pts with advanced solid tumors and exhibits clinical and pharmacological activity. A maximum tolerated dose has not been determined. NCT MedImmune LLC MedImmune LLC B.S. Glisson: Research funding for Clinical Trials from Pfizer, Bristol Myers Squibb, Oncomed, Stemcentrx, and Medimmune provided for MD Anderson. I am a PI on these grants. R. Leidner: Research is being supported by: Medimmune/ Astra Zeneca and Bristol-Myers Squibb R.L. Ferris: Paid member of Advisory Board (Ad-Hoc)- Merck, Celgene, Bristol Myers Squibb, AZ/Medimmune Research/Grant - VentiRx, Bristol Myers Squibb AZ/Medimmune. J. Powderly: Lion BioTechnologies, Juno Therapeutics, BlueBird Bio, Kite Pharma, ZioPharm Oncology, BMS, Genentech, EMD, Serono, AstraZeneca, InCyte, Macrogenics, Sequenom, Corvus, Carolina BioOncology Institute, PLLC, BioCytics Inc., Human Applications Lab, Merck. N. Rizvi: Consulting for AstraZeneca, Merck, Roche, Novartis, Lilly. Co-founder and shareholder, Gritstone Oncology. J.D. Norton: I am an employee of MedImmune LLC, a subsidiary of AstraZeneca, and hold restricted AstraZeneca stock shares. J. Burton: Employee of MedImmune Ltd. M.C. Lanasa: Employee of MedImmune LLC / AstraZeneca. S.P. Patel: Dr. Patel receives research funding from: MedImmune, Genentech, Pfizer, Amgen, Xcovery, Lilly, Bristol-Myers Squibb. He receives consulting fees from: Lilly, Pfizer. He receives speaking fees from: Boehringer Ingelheim, Merck. 1053PD - A first-in-human (FIH) study of PF (PF-8600) OX40 agonist in adult patients (pts) with select advanced malignancies

8 A. Diab (Houston, United States of America)A. El-Khoueiry (Los Angeles, United States of America) F. A. Eskens (Rotterdam, Netherlands)W. Ros (Amsterdam, Netherlands) J. A. Thompson (Seattle, United States of America)C. Konto (South San Francisco, United States of America) C. Bermingham (South San Francisco, United States of America)T. Joh (La Jolla, United States of America) K. Liao (La Jolla, United States of America)B. Ganguly (South San Francisco, United States of America) O. Hamid (Los Angeles, United States of America) Co-stimulation of activated T cells with agonistic monoclonal antibodies (mab) against the tumor necrosis factor receptor superfamily member OX40 offers a novel immunotherapeutic approach to cancer. OX40 engagement may co-stimulate effector T cells and deplete regulatory T cells, resulting in enhanced tumor immunity. PF-8600 is a fully human agonist IgG2 mab that targets OX40. A Phase 1, open label, multicenter study is ongoing to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of PF-8600 in pts with advanced melanoma, head and neck squamous cell, renal cell, or hepatocellular carcinoma. PF-8600 was administered intravenously at increasing doses ( mg/kg) every 2 weeks until disease progression or unacceptable toxicity. Additional biomarker cohorts (opened at each dose level except 0.01 mg/kg) enrolled pts who consented to baseline and on-treatment tumor biopsies for immune profiling by immunohistochemistry and RNAseq. As of 09 MAR 2016, 31 pts have enrolled in the dose-escalation phase of PF-8600 study: 0.01 mg/kg (2 pts), 0.1 mg/kg (10 pts), 0.3 mg/kg (8 pts), 1.5 mg/kg (7 pts) and 3 mg/kg (4 pts). 25.8% of patients received 4 prior therapies for advanced disease. No dose limiting toxicities, no drug-related or immune related grade (G) 3-5 adverse events (AEs) were observed. Drug-related AEs (DRAEs) were all G1/2 events and occurred in 21 pts (67.7%). The most common DRAEs were fatigue (29.0%) and decreased appetite (9.7%). Out of 25 pts evaluable for response, 1 pt experienced partial response (PR, -50%, confirmed), and 15 pts experienced stable disease (SD). 11 pts remain on treatment, and 5 patients continued treatment for >13 weeks. Assessment of peripheral blood lymphocyte indicated full OX40 receptor occupancy at 0.3 mg/kg, and maximal memory T cell proliferation at 0.1 and 0.3 mg/kg. These preliminary results demonstrate that PF-8600 is safe up to 3 mg/kg. Updated safety, antitumor activity, and biomarker data will be presented. NCT Pfizer, Inc. Pfizer, Inc.

9 A. Diab: Advisory board for Nektar Therapeutics. A. El-Khoueiry: Grants:NCI/NIH, CTEP, SWOG Consultant: Genentech, Bayer, Astra-Zeneca, Medimmune, Celgene, BMS, Transgene Speakers Bureau: Merrimack Contracted. Research: Pfizer,CeloNova, Novartis, AstraZeneca, BMS, Genentech, Pfizer, Astex, Daiichi Sankyo, Nektar, Exelixis, Chiltern. F.A. Eskens: Adboard for Baxalta, Merck, AMGEN. C. Konto: Pfizer's employee and shareholder. C. Bermingham: I have Pfizer stock as part of my 401K. T. Joh: I am Pfizer employee, and stock owner. K. Liao: Currently, I am employed by Pfizer Inc. and own Pfizer stock. B. Ganguly: I am a Pfizer employee and that I own Pfizer stock. O. Hamid: Consulting: Amgen, Novartis, Roche, BMS. Speaker: Amgen, BMS, Genentech, Merck, Novartis. Contracted Research: Astra Zeneca, BMS, Celldex, Genentech, Immunocore, Incyte, Merck, Merck-Serano, MedImmune, Novartis, Pfizer, Rinat, Roche. All other authors have declared no conflicts of interest. 1054PD - Phase I/II CANON study: oncolytic immunotherapy for the treatment of non-muscle invasive bladder (NMIBC) cancer using intravesical coxsackievirus A21 H. S. Pandha (Guildford, United Kingdom)N. Annels (Guildford, United Kingdom)M. Arif (Guildford, United Kingdom) H. Mostafid (Guildford, United Kingdom)S. Sandhu (Kingston, United Kingdom) K. Harrington (London, United Kingdom)A. Melcher (Leeds, United Kingdom)D. Mansfield (London, United Kingdom) G. Au (Sydney, Australia)M. Grose (Sydney, Australia)R. Karpathy (Sydney, Australia)D. Shafren (Sydney, Australia) CAVATAK is a novel, bio-selected Intercellular Adhesion Molecule 1 (ICAM-1) targeted immunotherapeutic Coxsackievirus A21 (CVA21). Surface ICAM-1 is up-regulated on NMIBC. CVA21 displays potent oncolytic activity against in vitro cultures of NMIBC cancer cells and ex-vivo human bladder tumor. Combining CVA21 with mitocycin C (MMC) synergistically enhances viral replication by increasing expression levels of ICAM-1. The CANON study investigated the tolerance of escalating intravesical (IV) doses of CVA21 in 16 first-line NMIBC cancer pts. Stage 1 Cohort 1 (n = 3) and Cohort 2 (n = 3), 8 8 pts received a single CVA21 administration at 1 x 10 and 3 x 10 TCID50, respectively. In 8 Cohort 3 (n = 3), pts received 2 doses of CVA21 at 3 x 10 TCID50. Stage 2: Cohort 1 8 (n = 3), pts received a single CVA21 dose of 3 x 10 TCID50 and Cohort 2 (n = 3) with 2 8 doses of CVA21 at 3 x 10 TCID50, both in combination with MMC (10mg). Cystoscopy photography was performed before and after treatment (tx). IV tx was followed by TURBT surgery after 8-11 days, with tissues analysed for CVA21 replication, apoptosis, evidence of viral-induced changes immune cell infiltrates (multi-spectral imaging) and immune checkpoint molecules. Data indicate tolerance of IV CVA21 tx. Serial cystoscopy identified viral-induced surface haemorrhage and immune inflammation of the tumor micro-environment. Virus replication within tumor was highlighted by detection of secondary viral load peaks in the urine. TURBT tissue analysis displayed marked tumor specific viral replication and evidence of viral-induced apoptotic cell death. NanoString analysis identified widespread increases in interferon (IFN), viral RNA and immune-checkpoint genes in CVA21-treated tissues compared to untreated historical controls.

10 Clinical activity of CVA21 was demonstrated by evidence of complete tumor response, viral replication and notable signs of tumor inflammation. The observed up-regulation of IFN/immune checkpoint genes provides evidence for the generation of both strong local and systemic anti-tumor immune responses. VLA-012 Viralytics Ltd Viralytics Ltd All authors have declared no conflicts of interest. 1056PD - Preventive dendritic cell vaccination in healthy Lynch syndrome mutation carriers H. Westdorp (Nijmegen, Netherlands)M. A. Gorris (Nijmegen, Netherlands)S. Boudewijns (Nijmegen, Netherlands) T. Bisseling (Nijmegen, Netherlands)A. L. De Goede (Nijmegen, Netherlands) M. M. Van Rossum (Nijmegen, Netherlands)M. J. Ligtenberg (Nijmegen, Netherlands) G. Schreibelt (Nijmegen, Netherlands)I. D. Nagtegaal (Nijmegen, Netherlands)C. G. Figdor (Nijmegen, Netherlands) W. Gerritsen (Nijmegen, Netherlands)N. Hoogerbrugge (Nijmegen, Netherlands) I. M. De Vries (Nijmegen, Netherlands) Lynch syndrome (LS) is an autosomal dominantly inherited syndrome caused by monoallelic germline aberrations affecting one of the DNA mismatch repair (MMR) genes. Defects in the DNA MMR pathway underlie the development of microsatellite instability in LS-associated cancer. The cumulative risk of colorectal cancer varies between 10-80% and is strongly associated with the causative germline defect. MMR deficiency in tumor DNA causes shifts in the translational reading frame resulting in the production of altered peptides, called neopeptides. These are considered foreign by the immune system. This was the rationale for a preventive neoantigen-based vaccination study with dendritic cells (DCs). DCs are the antigen-presenting cells of our immune system as a result of their naive T cell priming and T cell activation capabilities. We recruited HLA-A*02.01 positive patients known to be a germline MMR-gene mutation carrier without signs of LS-associated disease or more than 5-years beyond detection of a non-metastasized LS-associated cancer. The primary endpoint was to investigate the safety and feasibility of DC vaccinations. Secondary objectives were to evaluate whether monocyte-derived peptide-loaded DC can induce an immune response to the selected neoantigens (caspase-5 and TGF-ßRII) and the tumor-associated antigen carcinoembryonic antigen (CEA). All patients (n = 20) were recruited within a year. DC vaccinations were on average well tolerated. No participants were hospitalized during study treatment. In all vaccinated mutation carriers flu-like symptoms occurred. In 17 of 20 patients an injection site reaction

11 developed upon intradermal DC administration. One patient experienced grade 4 fever (>40 C > 24 hours), as a result study treatment was discontinued. In all tested patients a cellular immune response against the control antigen was seen. Functional neoantigen- or CEA-specific T cells were shown in the challenged skin upon DC vaccination in 15 of 20 patients. Preventive DC vaccination is feasible and safe in LS mutation carriers and functional neoantigen- and CEA-specific immune responses were shown. This study opens perspectives for future immunotherapy trials with the intention of cancer prevention. ClinicalTrials.gov NCT N/A This work was supported by Grant of the Netherlands Organization for Scientific Research (NWO), two Radboudumc Ph.D. grants and a Koningin Wilhelmina Onderzoeksprijs (KWO)-Grant KUN from the Dutch Cancer Society (KWF). CG Figdor is recipient of European Research Council (ERC) Advanced grant PATHFINDER (269019) and a NWO Spinoza grant. IJM de Vries is recipient of NWO Vici Grant W. Gerritsen: Consult for Aglaia Biomedical Ventures, Supervisory board for PsytoBe, Speakers fee from J&J and BMS, and Advisory boards for Amgen, BMS, Janssen-Cilag, Sanofi, Astellas, Bayer, and Merck. All other authors have declared no conflicts of interest. Invited discussant abstracts 1052PD, 1053PD, 1054PD and 1056PD S. Scholl Questions to discussant