eprintid: 26070
rev_number: 13
eprint_status: archive
userid: 1589
dir: disk0/00/02/60/70
datestamp: 2019-04-01 10:02:43
lastmod: 2019-05-13 12:44:43
status_changed: 2019-04-01 10:02:43
type: article
metadata_visibility: show
creators_name: Papachristofilou, Alexandros
creators_name: Hipp, Madeleine M.
creators_name: Klinkhardt, Ute
creators_name: Früh, Martin
creators_name: Sebastian, Martin
creators_name: Weiss, Christian
creators_name: Pless, Miklos
creators_name: Cathomas, Richard
creators_name: Hilbe, Wolfgang
creators_name: Pall, Georg
creators_name: Wehler, Thomas
creators_name: Alt, Jürgen
creators_name: Bischoff, Helge
creators_name: Geißler, Michael
creators_name: Griesinger, Frank
creators_name: Kallen, Karl-Josef
creators_name: Fotin-Mleczek, Mariola
creators_name: Schröder, Andreas
creators_name: Scheel, Birgit
creators_name: Muth, Anke
creators_name: Seibel, Tobias
creators_name: Stosnach, Claudia
creators_name: Doener, Fatma
creators_name: Hong, Henoch S.
creators_name: Koch, Sven D.
creators_name: Gnad-Vogt, Ulrike
creators_name: Zippelius, Alfred
title: Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer
subjects: ddc-610
divisions: i-950900
keywords: Clinical trial, Hypofractionated radiotherapy, Immunomonitoring, mRNA active cancer immunotherapy, Non-small cell lung cancer, BI1361849, CV9202
abstract: Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.

Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).

Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.

Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.

Trial registration: ClinicalTrials.gov, Identifier: NCT01915524.
date: 2019
publisher: BioMed Central
id_scheme: DOI
id_number: https://doi.org/10.1186/s40425-019-0520-5
ppn_swb: 1665114797
own_urn: urn:nbn:de:bsz:16-heidok-260704
language: eng
bibsort: PAPACHRISTPHASEIBEVA2019
full_text_status: public
publication: Journal for ImmunoTherapy of Cancer
volume: 7
number: 38
place_of_pub: London
pagerange: 1-14
issn: 2051-1426
citation:   Papachristofilou, Alexandros ; Hipp, Madeleine M. ; Klinkhardt, Ute ; Früh, Martin ; Sebastian, Martin ; Weiss, Christian ; Pless, Miklos ; Cathomas, Richard ; Hilbe, Wolfgang ; Pall, Georg ; Wehler, Thomas ; Alt, Jürgen ; Bischoff, Helge ; Geißler, Michael ; Griesinger, Frank ; Kallen, Karl-Josef ; Fotin-Mleczek, Mariola ; Schröder, Andreas ; Scheel, Birgit ; Muth, Anke ; Seibel, Tobias ; Stosnach, Claudia ; Doener, Fatma ; Hong, Henoch S. ; Koch, Sven D. ; Gnad-Vogt, Ulrike ; Zippelius, Alfred  (2019) Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer.  Journal for ImmunoTherapy of Cancer, 7 (38).  pp. 1-14.  ISSN 2051-1426     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/26070/1/40425_2019_Article_520.pdf