Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors
Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses.
This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide® ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy.
In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event.
Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.
KeywordsSurvivin EMD640744 Cancer vaccines Cancer immunotherapy
Ex vivo ELISpot
Ex vivo multimer staining
Fluorescence minus one
Immunologic-diagnostic intention-to-treat population
ELISpot following in vitro stimulation of PBMC
Multimer staining following in vitro stimulation of PBMC
Peripheral blood mononuclear cells
Treatment-emergent adverse event
The study was sponsored by Merck KGaA Darmstadt, Germany. The authors take full responsibility for the content of this publication. The authors would like to thank the patients, the investigators, co-investigators, and study teams at each of the participating centers and at Merck KGaA, Darmstadt, Germany. The contributions of Annett Hamann, the team of the cell sorting and immunomonitoring core unit in Erlangen and Daniela Eberts (Mainz), for their excellent technical assistance, are also gratefully acknowledged. Editorial assistance in the preparation of this manuscript was provided by Paola Accalai, International Medical Press, funded by Merck KGaA, Darmstadt, Germany.
Conflict of interest
Juergen Zieschang is a Merck employee. Ulf Forssmann was a Merck employee until the end of March 2013. Ulrike Gnad-Vogt was a Merck employee from 2005 to 2009 and received consultancy fees and a travel grant from Merck from 2009 to 2011 and has been a CureVac GmbH employee since 2011. All other authors declare that they have no competing interests.
- 2.Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C, Lal A, Wang CJ, Beaudry GA, Ciriello KM, Cook BP, Dufault MR, Ferguson AT, Gao Y, He TC, Hermeking H, Hiraldo SK, Hwang PM, Lopez MA, Luderer HF, Mathews B, Petroziello JM, Polyak K, Zawel L, Kinzler KW et al (1999) Analysis of human transcriptomes. Nat Genet 23(4):387–388. doi: 10.1038/70487 PubMedCrossRefGoogle Scholar
- 3.Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T (2001) Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 92(2):271–278. doi: 10.1002/1097-0142(20010715)92:2<271:AID-CNCR1319>3.0.CO;2-0 PubMedCrossRefGoogle Scholar
- 7.Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A (2000) High expression of survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 19(5):617–623PubMedCrossRefGoogle Scholar
- 10.Schmidt SM, Schag K, Müller MR, Weck MM, Appel S, Kanz L, Grünebach F, Brossart P (2003) Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells. Blood 102(2):571–576. doi: 10.1182/blood-2002-08-2554 PubMedCrossRefGoogle Scholar
- 14.Casati C, Dalerba P, Rivoltini L, Gallino G, Deho P, Rini F, Belli F, Mezzanzanica D, Costa A, Andreola S, Leo E, Parmiani G, Castelli C (2003) The apoptosis inhibitor protein survivin induces tumor-specific CD8+ and CD4+ T cells in colorectal cancer patients. Cancer Res 63(15):4507–4515PubMedGoogle Scholar
- 15.Tanaka M, Butler MO, Ansén S, Imataki O, Berezovskaya A, Nadler LM, Hirano N (2011) Induction of HLA-DP4-restricted anti-survivin Th1 and Th2 responses using an artificial antigen-presenting cell. Clin Cancer Res 17(16):5392–5401. doi: 10.1158/1078-0432.CCR-10-3083 PubMedCentralPubMedCrossRefGoogle Scholar
- 16.Becker JC, Andersen MH, Hofmeister-Müller V, Wobser M, Frey L, Sandig C, Walter S, Singh-Jasuja H, Kämpgen E, Opitz A, Zapatka M, Bröcker EB, Thor Straten P, Schrama D, Ugurel S (2012) Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma. Cancer Immunol Immunother 61(11):2091–2103. doi: 10.1007/s00262-012-1266-9 PubMedCentralPubMedCrossRefGoogle Scholar
- 17.Rapoport AP, Aqui NA, Stadtmauer EA, Vogl DT, Fang HB, Cai L, Janofsky S, Chew A, Storek J, Akpek G, Badros A, Yanovich S, Tan MT, Veloso E, Pasetti MF, Cross A, Philip S, Murphy H, Bhagat R, Zheng Z, Milliron T, Cotte J, Cannon A, Levine BL, Vonderheide RH, June CH (2011) Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood 117(3):788–797. doi: 10.1182/blood-2010-08-299396 PubMedCentralPubMedCrossRefGoogle Scholar
- 18.Honma I, Kitamura H, Torigoe T, Takahashi A, Tanaka T, Sato E, Hirohashi Y, Masumori N, Tsukamoto T, Sato N (2009) Phase I clinical study of anti-apoptosis protein survivin-derived peptide vaccination for patients with advanced or recurrent urothelial cancer. Cancer Immunol Immunother 58(11):1801–1807. doi: 10.1007/s00262-009-0691-x PubMedCrossRefGoogle Scholar
- 19.Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC (2006) Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol Immunother 55(10):1294–1298. doi: 10.1007/s00262-005-0102-x PubMedCrossRefGoogle Scholar
- 20.Tsuruma T, Iwayama Y, Ohmura T, Katsuramaki T, Hata F, Furuhata T, Yamaguchi K, Kimura Y, Torigoe T, Toyota N, Yagihashi A, Hirohashi Y, Asanuma H, Shimozawa K, Okazaki M, Mizushima Y, Nomura N, Sato N, Hirata K (2008) Clinical and immunological evaluation of anti-apoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer. J Transl Med 6:24. doi: 10.1186/1479-5876-6-24 PubMedCentralPubMedCrossRefGoogle Scholar
- 21.Miyazaki A, Kobayashi J, Torigoe T, Hirohashi Y, Yamamoto T, Yamaguchi A, Asanuma H, Takahashi A, Michifuri Y, Nakamori K, Nagai I, Sato N, Hiratsuka H (2011) Phase I clinical trial of survivin-derived peptide vaccine therapy for patients with advanced or recurrent oral cancer. Cancer Sci 102(2):324–329. doi: 10.1111/j.1349-7006.2010.01789.x PubMedCrossRefGoogle Scholar
- 22.Berntsen A, Trepiakas R, Wenandy L, Geertsen PF, thor Straten P, Andersen MH, Pedersen AE, Claesson MH, Lorentzen T, Johansen JS, Svane IM (2008) Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial. J Immunother 31(8):771–780. doi: 10.1097/CJI.0b013e3181833818 PubMedCrossRefGoogle Scholar
- 25.Ellebaek E, Engell-Noerregaard L, Iversen TZ, Froesig TM, Munir S, Hadrup SR, Andersen MH, Svane IM (2012) Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol Immunother 61(10):1791–1804. doi: 10.1007/s00262-012-1242-4 PubMedCrossRefGoogle Scholar
- 26.Kameshima H, Tsuruma T, Torigoe T, Takahashi A, Hirohashi Y, Tamura Y, Tsukahara T, Ichimiya S, Kanaseki T, Iwayama Y, Sato N, Hirata K (2011) Immunogenic enhancement and clinical effect by type-I interferon of anti-apoptotic protein, survivin-derived peptide vaccine, in advanced colorectal cancer patients. Cancer Sci 102(6):1181–1187. doi: 10.1111/j.1349-7006.2011.01918.x PubMedCrossRefGoogle Scholar
- 27.Widenmeyer M, Griesemann H, Stevanović S, Feyerabend S, Klein R, Attig S, Hennenlotter J, Wernet D, Kuprash DV, Sazykin AY, Pascolo S, Stenzl A, Gouttefangeas C, Rammensee HG (2012) Promiscuous survivin peptide induces robust CD4+ T-cell responses in the majority of vaccinated cancer patients. Int J Cancer 131(1):140–149. doi: 10.1002/ijc.26365 PubMedCrossRefGoogle Scholar
- 28.Otto K, Andersen MH, Eggert A, Keikavoussi P, Pedersen LØ, Rath JC, Böck M, Bröcker EB, Straten PT, Kämpgen E, Becker JC (2005) Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin. Vaccine 23(7):884–889. doi: 10.1016/j.vaccine.2004.08.007 PubMedCrossRefGoogle Scholar
- 29.Tsuruma T, Hata F, Torigoe T, Furuhata T, Idenoue S, Kurotaki T, Yamamoto M, Yagihashi A, Ohmura T, Yamaguchi K, Katsuramaki T, Yasoshima T, Sasaki K, Mizushima Y, Minamida H, Kimura H, Akiyama M, Hirohashi Y, Asanuma H, Tamura Y, Shimozawa K, Sato N, Hirata K (2004) Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer. J Transl Med 2:19. doi: 10.1186/1479-5876-2-19 PubMedCentralPubMedCrossRefGoogle Scholar
- 32.Karanikas V, Soukou F, Kalala F, Kerenidi T, Grammoustianou ES, Gourgoulianis KI, Germenis AE (2008) Baseline levels of CD8+ T cells against survivin and survivin-2B in the blood of lung cancer patients and cancer-free individuals. Clin Immunol 129(2):230–240. doi: 10.1016/j.clim.2008.07.024 PubMedCrossRefGoogle Scholar
- 33.Britten CM, Janetzki S, Butterfield LH, Ferrari G, Gouttefangeas C, Huber C, Kalos M, Levitsky HI, Maecker HT, Melief CJ, O’Donnell-Tormey J, Odunsi K, Old LJ, Ottenhoff TH, Ottensmeier C, Pawelec G, Roederer M, Roep BO, Romero P, van der Burg SH, Walter S, Hoos A, Davis MM (2012) T cell assays and MIATA: the essential minimum for maximum impact. Immunity 37(1):1–2. doi: 10.1016/j.immuni.2012.07.010 PubMedCrossRefGoogle Scholar
- 34.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) Elispot proficiency panel of the CVC immune assay working group. Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI). Cancer Immunol Immunother 57(3):303–315. doi: 10.1007/s00262-007-0380-6 PubMedCentralPubMedCrossRefGoogle Scholar
- 36.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, 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(3):205–216. doi: 10.1093/jnci/92.3.205 PubMedCrossRefGoogle Scholar
- 37.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. doi: 10.1016/j.ejca.2008.10.026 PubMedCrossRefGoogle Scholar
- 38.Bernatchez C, Zhu K, Li Y, Andersson H, Ionnides C, Fernandez-Vina M, Cano P, Cooper L, Abbruzzese J, Hwu P, Chang DZ, Radvanyi LG (2011) Altered decamer and nonamer from an HLA-A0201-restricted epitope of survivin differentially stimulate T-cell responses in different individuals. Vaccine 29(16):3021–3030. doi: 10.1016/j.vaccine.2011.01.115 PubMedCentralPubMedCrossRefGoogle Scholar