A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer

Springer Science and Business Media LLC - Tập 68 - Trang 799-812 - 2019
Martin Sebastian1,2, Andreas Schröder3,4, Birgit Scheel3, Henoch S. Hong3,4, Anke Muth3, Lotta von Boehmer5,6, Alfred Zippelius7, Frank Mayer8,9, Martin Reck10, Djordje Atanackovic11,12, Michael Thomas13, Folker Schneller14, Jan Stöhlmacher15,16, Helga Bernhard17, Andreas Gröschel18,19, Thomas Lander3, Jochen Probst3,20, Tanja Strack3, Volker Wiegand3, Ulrike Gnad-Vogt3, Karl-Josef Kallen3,21, Ingmar Hoerr3, Florian von der Muelbe3, Mariola Fotin-Mleczek3, Alexander Knuth5,22, Sven D. Koch3,23
1University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
2Medizinische Klinik II, Hämatologie/Onkologie, Rheumatologie, Infektiologie, HIV Klinikum der J.W. Goethe-Universität Frankfurt, Frankfurt am Main, Germany
3CureVac AG, Tübingen, Germany
4Merck KGaA, Darmstadt, Germany
5Klinik für Onkologie, UniversitätsSpital Zürich, Zurich, Switzerland
6Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, USA
7Klinik für Onkologie, Universitätsspital Basel, Basel, Switzerland
8Universitätsklinikum Tübingen, Tübingen, Germany
9Praxis und Tagesklinik, Friedrichshafen, Germany
10LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
11Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
12Huntsman Cancer Institute, University of Utah, Salt Lake City, USA
13Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
14Klinikum rechts der Isar der TUM, Munich, Germany
15Universitätsklinikum Carl Gustav Carus, Dresden, Germany
16Tumorgenetik Bonn, Bonn, Germany
17Klinikum Darmstadt GmbH, Darmstadt, Germany
18Universitätsklinikum Aachen, Aachen, Germany
19Clemenshospital, Münster, Germany
20Sandoz GmbH, Langkampfen, Austria
21Kallen Medical Innovation GmbH, Frechen, Germany
22National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar
23Sandoz Biopharmaceuticals, Department of Clinical Bioanalytics, Oberhaching, Germany

Tóm tắt

CV9201 is an RNActive®-based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400–1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD+CD38hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8–6.3) and 10.8 months (8.1–16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation.

Tài liệu tham khảo

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