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J Immunother Cancer. 2019 Feb 8;7(1):38. doi: 10.1186/s40425-019-0520-5.

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.

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Clinic of Radiotherapy and Radiation Oncology, University Hospital Basel, Basel, Switzerland.
CureVac AG, Tübingen, Germany.
Hospital of St Gallen, St Gallen and University of Bern, Bern, Switzerland.
University Hospital Frankfurt, Frankfurt, Germany.
Cantonal Hospital of Winterthur, Winterthur, Switzerland.
Hospital Graubünden, Chur, Switzerland.
Medical Department, Center for Oncology and Hematology, Wilhelminenspital, Wien, Austria.
University Hospital Innsbruck, Innsbruck, Austria.
Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany.
Thoraxklinik Heidelberg gGmbH, Heidelberg, Germany.
Klinik für Allg Innere Medizin, Onkolologie/ Hämatologie, Gastroenterologie, Infektiologie, Esslingen, Germany.
Department Hematology and Oncology, Pius Hospital University, Oldenburg, Germany.
Department Internal Medicine-Oncology, Medical Campus University of Oldenburg, Oldenburg, Germany.
eTheRNA Immunotherapies NV, Niel, Belgium.
Medical Oncology, University Hospital Basel, Basel, Switzerland.



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.


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).


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.


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

TRIAL REGISTRATION: identifier: NCT01915524 .


BI1361849; CV9202; Clinical trial; Hypofractionated radiotherapy; Immunomonitoring; Non-small cell lung cancer; mRNA active cancer immunotherapy

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