TY  - JOUR
A1  - Papachristofilou, Alexandros
A1  - Hipp, Madeleine M.
A1  - Klinkhardt, Ute
A1  - Früh, Martin
A1  - Sebastian, Martin
A1  - Weiß, Christian
A1  - Pless, Miklos
A1  - Cathomas, Richard
A1  - Hilbe, Wolfgang
A1  - Pall, Georg
A1  - Wehler, Thomas
A1  - Alt, Jürgen
A1  - Bischoff, Helge
A1  - Geißler, Michael
A1  - Griesinger, Frank
A1  - Kallen, Karl-Josef
A1  - Fotin-Mleczek, Mariola
A1  - Schröder, Andreas
A1  - Scheel, Birgit
A1  - Muth, Anke
A1  - Seibel, Tobias
A1  - Stosnach, Claudia
A1  - Doener, Fatma
A1  - Hong, Henoch Sangjoon
A1  - Koch, Sven D.
A1  - Gnad-Vogt, Ulrike
A1  - Zippelius, Alfred
T1  - 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
T2  - Journal for ImmunoTherapy of Cancer
N2  - 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.
KW  - Clinical trial
KW  - Hypofractionated radiotherapy
KW  - Immunomonitoring
KW  - mRNA active cancer immunotherapy
KW  - Non-small cell lung cancer
KW  - BI1361849
KW  - CV9202
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/49087
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-490878
SN  - 2051-1426
N1  - Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
VL  - 7
IS  - 1, Art. 38
SP  - 1
EP  - 14
PB  - BioMed Central
CY  - London
ER  -