A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer
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.
KeywordsActive cancer immunotherapy mRNA Non-small cell lung cancer Immunomonitoring Clinical trial CV9201
Melanoma antigen family C1/C2
National Cancer Institute Common Terminology Criteria for Adverse Events
New York esophageal squamous cell carcinoma-1
Recommended phase II dose
Thyroid stimulating hormone
We thank all patients, staff, and investigators of the participating hospitals. We thank Jamie Ashman of Prism Ideas for Editorial support in the preparation of this manuscript and Helen Dietrich, Simone Eppler and Kathrin Hoch for providing technical support for the study including sample preparation and logistics, and immunomonitoring. Furthermore, we thank Thomas Dörner and Thomas Woelfel for scientific advice, Gerd Rippin for statistical advice, and Eray Goekkurt for medical support.
MS, BS, JP, TL, UG-V, K-JK, IH, and MF-M conceived, designed and supervised the study. MS, LB, AZ, FM, MR, DA, MT, FS, JS, HB, AG, and AK recruited patients and provided clinical samples. AS, BS, AM, HSH, TS, VW, FM and SDK acquired and analyzed the data. AS, BS, AM, HSH, and SDK drafted the manuscript. All authors read and approved the final version of the paper.
This study, and editorial support for the preparation of this manuscript, were funded by CureVac AG. The sponsor was involved in study design, data collection, analysis, and interpretation, writing of the article, and in the decision to submit the article for publication.
Compliance with ethical standards
Conflict of interest
Martin Sebastian reports personal fees from Lilly and Roche during the conduct of the study, and personal fees from Boehringer-Ingelheim, Pfizer, Astra-Zeneca, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), and Novartis, outside the submitted work. Alfred Zippelius reports grants from Roche, Actelion, Piqur, Secarna, and Beyondsprings, and personal fees from BMS, MSD, and NBE Therapeutics outside the submitted work. Martin Reck reports personal fees from Roche, Lilly, Boehringer-Ingelheim, BMS, AstraZeneca, MSD, Novartis, Pfizer, and Celgene, outside the submitted work. Alexander Knuth reports a former scientific advisory role for CureVac AG and is co-inventor on multiple patents of Ludwig Institute for Cancer Research (LICR) related to NY-ESO-1 and MAGE, partly licensed to multiple companies including CureVac AG. Birgit Scheel, Anke Muth, Tanja Strack, Volker Wiegand, Ulrike Gnad-Vogt, Ingmar Hoerr, Florian von der Muelbe and Mariola Fotin-Mleczek are employees of CureVac AG. Thomas Lander, Andreas Schröder, Henoch S. Hong, Jochen Probst, Karl-Josef Kallen and Sven D. Koch were employees of CureVac GmbH/AG. Thomas Lander was a clinical consultant to CureVac GmbH until 2012. Thomas Lander, Jochen Probst, and Ingmar Hoerr jointly hold a patent related to the use of mRNA vaccines for treating lung cancer (WO2009/046974) filed in several jurisdictions (issued in some and pending in others). Ulrike Gnad-Vogt, Karl-Josef Kallen, and Mariola Fotin-Mleczek jointly hold a patent related to the use of mRNA vaccines for treating lung cancer (WO2015/024666) filed in several jurisdictions (still pending). All other authors declare no conflicts of interest.
Ethical approval and ethical standards
The protocol was approved by the regulatory authorities, a central ethics committee for the 12 participating centers in Germany (Ethikkommission bei der Landesärztekammer Hessen, Frankfurt am Main, Germany - Approval Number: FF 2/2009) and two local ethics committees for the two participating centers in Switzerland (Spezial-Unterkommission (SPUK) Innere Medizin, Kantonale Ethikkommission UniversitätsSpital Zürich, Zürich, Switzerland - Approval Number: EK-1639, and Ethikkommission beider Basel (EKBB), Universitätsspital Basel, Basel, Switzerland - Approval Number: 20/09). The study was conducted in accordance with Good Clinical Practice guidelines (EudraCT No.: 2008-007785-39). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent on being treated as well as on the use of generated data for research purposes and publication was obtained from all individual participants included in the study.
- 1.Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren FO, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135CrossRefGoogle Scholar
- 2.Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, Powderly JD, Heist RS, Carvajal RD, Jackman DM, Sequist LV, Smith DC, Leming P, Carbone DP, Pinder-Schenck MC, Topalian SL, Hodi FS, Sosman JA, Sznol M, McDermott DF, Pardoll DM, Sankar V, Ahlers CM, Salvati M, Wigginton JM, Hellmann MD, Kollia GD, Gupta AK, Brahmer JR (2015) Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 33:2004–2012CrossRefGoogle Scholar
- 3.Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf FF, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639CrossRefGoogle Scholar
- 4.Hellmann MD, Rizvi NA, Goldman JW, Gettinger SN, Borghaei H, Brahmer JR, Ready NE, Gerber DE, Chow LQ, Juergens RA, Shepherd FA, Laurie SA, Geese WJ, Agrawal S, Young TC, Li X, Antonia SJ (2017) Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18:31–41CrossRefGoogle Scholar
- 6.Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, Horger MS, Maksimovic O, Stenzl A, Hoerr I, Rammensee HG, Holderried TAW, Kanz L, Pascolo S, Brossart P (2011) Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol Ther 19:990–999CrossRefGoogle Scholar
- 7.Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, Horger MS, Maksimovic O, Stenzl A, Hoerr I, Rammensee HG, Holderried TA, Kanz L, Pascolo S, Brossart P (2016) Long-term survival correlates with immunological responses in renal cell carcinoma patients treated with mRNA-based immunotherapy. Oncoimmunology 5:e1108511CrossRefGoogle Scholar
- 13.Kübler H, Scheel B, Gnad-Vogt U, Miller K, Schultze-Seemann W, Vom DF, Parmiani G, Hampel C, Wedel S, Trojan L, Jocham D, Maurer T, Rippin G, Fotin-Mleczek M, von der MF, Probst, Hoerr J, Kallen I, Lander KJ, Stenzl T A (2015) Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study. J Immunother Cancer 3:26CrossRefGoogle Scholar
- 20.Weide B, Martens A, Zelba H, Stutz C, Derhovanessian E, Di Giacomo AM, Maio M, Sucker A, Schilling B, Schadendorf D, Buttner P, Garbe C, Pawelec G (2014) Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory T cells and NY-ESO-1- or melan-A-specific T cells. Clin Cancer Res 20:1601–1609CrossRefGoogle Scholar
- 22.Andersen MH, Pedersen LO, Becker JC, Straten PT (2001) Identification of a cytotoxic T lymphocyte response to the apoptosis inhibitor protein survivin in cancer patients. Cancer Res 61:869–872Google Scholar
- 24.Damelin M, Geles KG, Follettie MT, Yuan P, Baxter M, Golas J, DiJoseph JF, Karnoub M, Huang S, Diesl V, Behrens C, Choe SE, Rios C, Gruzas J, Sridharan L, Dougher M, Kunz A, Hamann PR, Evans D, Armellino D, Khandke K, Marquette K, Tchistiakova L, Boghaert ER, Abraham RT, Wistuba II, Zhou BB (2011) Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells. Cancer Res 71:4236–4246CrossRefGoogle Scholar
- 25.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van GM, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefGoogle Scholar
- 26.Janetzki S, Panageas KS, Ben-Porat L, Boyer J, Britten CM, Clay TM, Kalos M, Maecker HT, Romero P, Yuan J, Kast WM, Hoos A (2008) Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI). Cancer Immunol Immunother 57:303–315CrossRefGoogle Scholar
- 29.Hong HS, Koch SD, Scheel B, Gnad-Vogt U, Schroder A, Kallen KJ, Wiegand V, Backert L, Kohlbacher O, Hoerr I, Fotin-Mleczek M, Billingsley JM (2016) Distinct transcriptional changes in non-small cell lung cancer patients associated with multi-antigenic RNActive(R) CV9201 immunotherapy. Oncoimmunology 5:e1249560CrossRefGoogle Scholar
- 30.Hazama S, Nakamura Y, Takenouchi H, Suzuki N, Tsunedomi R, Inoue Y, Tokuhisa Y, Iizuka N, Yoshino S, Takeda K, Shinozaki H, Kamiya A, Furukawa H, Oka M (2014) A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome. J Transl Med 12:63CrossRefGoogle Scholar
- 31.Aruga A, Takeshita N, Kotera Y, Okuyama R, Matsushita N, Ohta T, Takeda K, Yamamoto M (2013) Long-term vaccination with multiple peptides derived from cancer-testis antigens can maintain a specific T-cell response and achieve disease stability in advanced biliary tract cancer. Clin Cancer Res 19:2224–2231CrossRefGoogle Scholar
- 32.Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, Hilf N, Schoor O, Fritsche J, Mahr A, Maurer D, Vass V, Trautwein C, Lewandrowski P, Flohr C, Pohla H, Stanczak JJ, Bronte V, Mandruzzato S, Biedermann T, Pawelec G, Derhovanessian E, Yamagishi H, Miki T, Hongo F, Takaha N, Hirakawa K, Tanaka H, Stevanovic S, Frisch J, Mayer-Mokler A, Kirner A, Rammensee HG, Reinhardt C, Singh-Jasuja H (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261CrossRefGoogle Scholar
- 33.Zandberg DP, Rollins S, Goloubeva O, Morales RE, Tan M, Taylor R, Wolf JS, Schumaker LM, Cullen KJ, Zimrin A, Ord R, Lubek JE, Suntharalingam M, Papadimitriou JC, Mann D, Strome SE, Edelman MJ (2015) A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN). Cancer Immunol Immunother 64:367–379CrossRefGoogle Scholar
- 38.Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE, Bosquee L, Trigo JM, Spira A, Tremblay L, Nyman J, Ramlau R, Wickart-Johansson G, Ellis P, Gladkov O, Pereira JR, Eberhardt WE, Helwig C, Schroder A, Shepherd FA (2014) Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 15:59–68CrossRefGoogle Scholar
- 39.Vansteenkiste JF, Cho BC, Vanakesa T, De PT, Zielinski M, Kim MS, Jassem J, Yoshimura M, Dahabreh J, Nakayama H, Havel L, Kondo H, Mitsudomi T, Zarogoulidis K, Gladkov OA, Udud K, Tada H, Hoffman H, Bugge A, Taylor P, Gonzalez EE, Liao ML, He J, Pujol JL, Louahed J, Debois M, Brichard V, Debruyne C, Therasse P, Altorki N (2016) Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:822–835CrossRefGoogle Scholar
- 40.Giaccone G, Bazhenova LA, Nemunaitis J, Tan M, Juhasz E, Ramlau R, van den Heuvel MM, Lal R, Kloecker GH, Eaton KD, Chu Q, Dunlop DJ, Jain M, Garon EB, Davis CS, Carrier E, Moses SC, Shawler DL, Fakhrai H (2015) A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 51:2321–2329CrossRefGoogle Scholar
- 41.Sebastian M, Papachristofilou A, Weiss C, Fruh M, Cathomas R, Hilbe W, Wehler T, Rippin G, Koch SD, Scheel B, Fotin-Mleczek M, Heidenreich R, Kallen KJ, Gnad-Vogt U, Zippelius A (2014) Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive(R)) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer. BMC Cancer 14:748CrossRefGoogle Scholar
- 42.Bohnhorst JO, Bjorgan MB, Thoen JE, Natvig JB, Thompson KM (2001) Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjogren’s syndrome. J Immunol 167:3610–3618CrossRefGoogle Scholar
- 47.Alberer M, Gnad-Vogt U, Hong HS, Mehr KT, Backert L, Finak G, Gottardo R, Bica MA, Garofano A, Koch SD, Fotin-Mleczek M, Hoerr I, Clemens R von SF (2017) Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet 390:1511–1520CrossRefGoogle Scholar
- 49.Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, Meng M, Fritz D, Vascotto F, Hefesha H, Grunwitz C, Vormehr M, Husemann Y, Selmi A, Kuhn AN, Buck J, Derhovanessian E, Rae R, Attig S, Diekmann J, Jabulowsky RA, Heesch S, Hassel J, Langguth P, Grabbe S, Huber C, Tureci O, Sahin U (2016) Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534:396–401CrossRefGoogle Scholar
- 50.Bahl K, Senn JJ, Yuzhakov O, Bulychev A, Brito LA, Hassett KJ, Laska ME, Smith M, Almarsson O, Thompson J, Ribeiro AM, Watson M, Zaks T, Ciaramella G (2017) Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol Ther 25:1316–1327CrossRefGoogle Scholar
- 51.Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Lower M, Bukur V, Tadmor AD, Luxemburger U, Schrors B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Muller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Bruck AK, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Holler C, Utikal J, Huber C, Loquai C, Tureci O (2017) Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547:222–226CrossRefGoogle Scholar