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Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors

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Abstract

Purpose

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.

Experimental design

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.

Results

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.

Conclusions

Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

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Abbreviations

AE:

Adverse event

evELISpot:

Ex vivo ELISpot

evMMS:

Ex vivo multimer staining

FMO:

Fluorescence minus one

ID:

Immunologic-diagnostic population

ID-ITT:

Immunologic-diagnostic intention-to-treat population

ITT:

Safety/intention-to-treat population

ivsELISpot:

ELISpot following in vitro stimulation of PBMC

ivsMMS:

Multimer staining following in vitro stimulation of PBMC

PBMC:

Peripheral blood mononuclear cells

TEAE:

Treatment-emergent adverse event

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Acknowledgments

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.

Author information

Author notes

  1. Ulrike Gnad-Vogt

    Present address: CureVac GmbH, Frankfurt a.M., Germany

  2. Ulf Forssmann

    Present address: Bayer Pharma AG, Berlin, Germany

Authors and Affiliations

  1. III. Medical Clinic/Hematology/Oncology, Verfügungsgebäude f. Forschung and Entwicklung, University Medical Center, Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 63, 55131, Mainz, Germany

    Volker Lennerz & Thomas Woelfel

  2. Department of Dermatology, University Hospital of Erlangen, Erlangen, Germany

    Stefanie Gross & Eckhart Kaempgen

  3. IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    Elisa Gallerani & Cristiana Sessa

  4. Clinical Research Unit of the Foundation Dr. Henri Dubois-Ferrière Dinu Lipatti, Oncology Center, Hôpitaux Universitaires de Genève (HUG), Geneva, Switzerland

    Nicolas Mach

  5. Onkologie/Hämatologie, Kantonsspital, St. Gallen, Switzerland

    Steffen Boehm & Dagmar Hess

  6. Department of Oncology, University Hospital Zurich, Zurich, Switzerland

    Lotta von Boehmer & Alexander Knuth

  7. Universitätsklinik und Poliklinik für Medizinische Onkologie, Inselspital, Bern, Switzerland

    Adrian F. Ochsenbein

  8. Merck KGaA, Darmstadt, Germany

    Ulrike Gnad-Vogt & Juergen Zieschang

  9. Merck Serono S.A.—Geneva, Geneva, Switzerland

    Ulf Forssmann

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  1. Volker Lennerz
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Correspondence to Volker Lennerz.

Additional information

Volker Lennerz, Stefanie Gross, Ulrike Gnad-Vogt, Ulf Forssmann, Thomas Woelfel, and Eckhart Kaempgen have contributed equally to this work.

Study number/Clinicaltrials.gov reference: EMR 200032-001/NCT01012102.

The authors of this paper report on their T cell assays transparently and comprehensively as per field-wide consensus, allowing the community a full understanding and interpretation of presented data as well as a comparison of data between groups. The electronic supplementary materials of this publication include a MIATA checklist.

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Lennerz, V., Gross, S., Gallerani, E. et al. Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors. Cancer Immunol Immunother 63, 381–394 (2014). https://doi.org/10.1007/s00262-013-1516-5

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