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.
- Papachristofilou A Clinic of Radiotherapy and Radiation Oncology, University Hospital Basel, Basel, Switzerland.
- Hipp MM CureVac AG, Tübingen, Germany.
- Klinkhardt U CureVac AG, Tübingen, Germany.
- Früh M Hospital of St Gallen, St Gallen and University of Bern, Bern, Switzerland.
- Sebastian M University Hospital Frankfurt, Frankfurt, Germany.
- Weiss C University Hospital Frankfurt, Frankfurt, Germany.
- Pless M Cantonal Hospital of Winterthur, Winterthur, Switzerland.
- Cathomas R Hospital Graubünden, Chur, Switzerland.
- Hilbe W Medical Department, Center for Oncology and Hematology, Wilhelminenspital, Wien, Austria.
- Pall G University Hospital Innsbruck, Innsbruck, Austria.
- Wehler T Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany.
- Alt J Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany.
- Bischoff H Thoraxklinik Heidelberg gGmbH, Heidelberg, Germany.
- Geißler M Klinik für Allg Innere Medizin, Onkolologie/ Hämatologie, Gastroenterologie, Infektiologie, Esslingen, Germany.
- Griesinger F Department Hematology and Oncology, Pius Hospital University, Oldenburg, Germany.
- Kallen KJ eTheRNA Immunotherapies NV, Niel, Belgium.
- Fotin-Mleczek M CureVac AG, Tübingen, Germany.
- Schröder A CureVac AG, Tübingen, Germany.
- Scheel B CureVac AG, Tübingen, Germany.
- Muth A CureVac AG, Tübingen, Germany.
- Seibel T CureVac AG, Tübingen, Germany.
- Stosnach C CureVac AG, Tübingen, Germany.
- Doener F CureVac AG, Tübingen, Germany.
- Hong HS CureVac AG, Tübingen, Germany.
- Koch SD CureVac AG, Tübingen, Germany.
- Gnad-Vogt U CureVac AG, Tübingen, Germany.
- Zippelius A Medical Oncology, University Hospital Basel, Basel, Switzerland. Alfred.Zippelius@usb.ch.
- 2019-02-10
Published in:
- Journal for immunotherapy of cancer. - 2019
BI1361849
CV9202
Clinical trial
Hypofractionated radiotherapy
Immunomonitoring
Non-small cell lung cancer
mRNA active cancer immunotherapy
Adjuvants, Immunologic
Adult
Aged
Aged, 80 and over
Antigens, Neoplasm
Antineoplastic Agents
Carcinoma, Non-Small-Cell Lung
Combined Modality Therapy
Female
Humans
Immunotherapy
Lung Neoplasms
Male
Membrane Glycoproteins
Membrane Proteins
Middle Aged
Mucin-1
Neoplasm Proteins
Pemetrexed
Protamines
RNA, Messenger
Survivin
English
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 .
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 .
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s40425-019-0520-5
- PMID 30736848
- Persistent URL
- https://sonar.ch/global/documents/201476
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