Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

Steffen Walter; Toni Weinschenk; Arnulf Stenzl; Romuald Zdrojowy; Anna Pluzanska; Cezary Szczylik; Michael Staehler; Wolfram Brugger; Pierre Yves Dietrich; Regina Mendrzyk; Norbert Hilf; Oliver Schoor; Jens Fritsche; Andrea Mahr; Dominik Maurer; Verona Vass; Claudia Trautwein; Peter Lewandrowski; Christian Flohr; Heike Pohla; Janusz J. Stanczak; Vincenzo Bronte; Susanna Mandruzzato; Tilo Biedermann; Graham Pawelec; Evelyna Derhovanessian; Hisakazu Yamagishi; Tsuneharu Miki; Fumiya Hongo; Natsuki Takaha; Kosei Hirakawa; Hiroaki Tanaka; Stefan Stevanovic; Jürgen Frisch; Andrea Mayer-Mokler; Alexandra Kirner; Hans Georg Rammensee; Carsten Reinhardt; Harpreet Singh-Jasuja

doi:10.1038/nm.2883

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

Steffen Walter, Toni Weinschenk, Arnulf Stenzl, Romuald Zdrojowy, Anna Pluzanska, Cezary Szczylik, Michael Staehler, Wolfram Brugger, Pierre Yves Dietrich, Regina Mendrzyk, Norbert Hilf, Oliver Schoor, Jens Fritsche, Andrea Mahr, Dominik Maurer, Verona Vass, Claudia Trautwein, Peter Lewandrowski, Christian Flohr, Heike PohlaJanusz J. Stanczak, Vincenzo Bronte, Susanna Mandruzzato, Tilo Biedermann, Graham Pawelec, Evelyna Derhovanessian, Hisakazu Yamagishi, Tsuneharu Miki, Fumiya Hongo, Natsuki Takaha, Kosei Hirakawa, Hiroaki Tanaka, Stefan Stevanovic, Jürgen Frisch, Andrea Mayer-Mokler, Alexandra Kirner, Hans Georg Rammensee, Carsten Reinhardt, Harpreet Singh-Jasuja

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Abstract

IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-Associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02 + subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3) + regulatory T (T reg) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T reg cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

Original language	English
Pages (from-to)	1254-1261
Number of pages	8
Journal	Nature Medicine
Volume	18
Issue number	8
DOIs	https://doi.org/10.1038/nm.2883
State	Published - Aug 2012
Externally published	Yes

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10.1038/nm.2883

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Walter, S., Weinschenk, T., Stenzl, A., Zdrojowy, R., Pluzanska, A., Szczylik, C., Staehler, M., Brugger, W., Dietrich, P. Y., Mendrzyk, R., Hilf, N., Schoor, O., Fritsche, J., Mahr, A., Maurer, D., Vass, V., Trautwein, C., Lewandrowski, P., Flohr, C., ... Singh-Jasuja, H. (2012). Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nature Medicine, 18(8), 1254-1261. https://doi.org/10.1038/nm.2883

@article{bcdb6b932e1f46358601f5c55918cfc1,

title = "Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival",

abstract = "IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-Associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02 + subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3) + regulatory T (T reg) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T reg cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.",

author = "Steffen Walter and Toni Weinschenk and Arnulf Stenzl and Romuald Zdrojowy and Anna Pluzanska and Cezary Szczylik and Michael Staehler and Wolfram Brugger and Dietrich, {Pierre Yves} and Regina Mendrzyk and Norbert Hilf and Oliver Schoor and Jens Fritsche and Andrea Mahr and Dominik Maurer and Verona Vass and Claudia Trautwein and Peter Lewandrowski and Christian Flohr and Heike Pohla and Stanczak, {Janusz J.} and Vincenzo Bronte and Susanna Mandruzzato and Tilo Biedermann and Graham Pawelec and Evelyna Derhovanessian and Hisakazu Yamagishi and Tsuneharu Miki and Fumiya Hongo and Natsuki Takaha and Kosei Hirakawa and Hiroaki Tanaka and Stefan Stevanovic and J{\"u}rgen Frisch and Andrea Mayer-Mokler and Alexandra Kirner and Rammensee, {Hans Georg} and Carsten Reinhardt and Harpreet Singh-Jasuja",

note = "Funding Information: We thank all investigators and patients participating in the clinical studies. Samples of healthy donors were kindly provided by D. Wernet (Institute of Clinical and Experimental Transfusion Medicine, T{\"u}bingen). The cell line K562-A2 was kindly provided by C. Britten (Tumorvakzinezentrum Mainz). This work was supported by the German {\textquoteleft}F{\"o}rderprogramm Biotechnologie Baden-W{\"u}rttemberg{\textquoteright} projects 720.830-1-1/46b and 720.830-3-9, the German {\textquoteleft}Fort{\"u}ne{\textquoteright} project 1862-0-0, the German {\textquoteleft}Deutsche Forschungsgemeinschaft Sonderforschungsbereich 685{\textquoteright} projects A6, C5 and C9, the German {\textquoteleft}Bundesministerium f{\"u}r Bildung und Forschung{\textquoteright} project 0315890F, the Italian {\textquoteleft}Fondazione Cassa di Risparmio di Verona, Vicenza, Belluno e Ancona{\textquoteright} and the Italian {\textquoteleft}Associazione Italiana Ricerca sul Cancro{\textquoteright} (grant 6599). We thank H. Schild for providing critical input to the manuscript and the members of the Immatics{\textquoteright} Scientific Advisory Board and the Data Safety Monitoring Board for critical input throughout the development program.",

year = "2012",

month = aug,

doi = "10.1038/nm.2883",

language = "English",

volume = "18",

pages = "1254--1261",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "8",

}

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', Nature Medicine, vol. 18, no. 8, pp. 1254-1261. https://doi.org/10.1038/nm.2883

TY - JOUR

T1 - Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

AU - Walter, Steffen

AU - Weinschenk, Toni

AU - Stenzl, Arnulf

AU - Zdrojowy, Romuald

AU - Pluzanska, Anna

AU - Szczylik, Cezary

AU - Staehler, Michael

AU - Brugger, Wolfram

AU - Dietrich, Pierre Yves

AU - Mendrzyk, Regina

AU - Hilf, Norbert

AU - Schoor, Oliver

AU - Fritsche, Jens

AU - Mahr, Andrea

AU - Maurer, Dominik

AU - Vass, Verona

AU - Trautwein, Claudia

AU - Lewandrowski, Peter

AU - Flohr, Christian

AU - Pohla, Heike

AU - Stanczak, Janusz J.

AU - Bronte, Vincenzo

AU - Mandruzzato, Susanna

AU - Biedermann, Tilo

AU - Pawelec, Graham

AU - Derhovanessian, Evelyna

AU - Yamagishi, Hisakazu

AU - Miki, Tsuneharu

AU - Hongo, Fumiya

AU - Takaha, Natsuki

AU - Hirakawa, Kosei

AU - Tanaka, Hiroaki

AU - Stevanovic, Stefan

AU - Frisch, Jürgen

AU - Mayer-Mokler, Andrea

AU - Kirner, Alexandra

AU - Rammensee, Hans Georg

AU - Reinhardt, Carsten

AU - Singh-Jasuja, Harpreet

N1 - Funding Information: We thank all investigators and patients participating in the clinical studies. Samples of healthy donors were kindly provided by D. Wernet (Institute of Clinical and Experimental Transfusion Medicine, Tübingen). The cell line K562-A2 was kindly provided by C. Britten (Tumorvakzinezentrum Mainz). This work was supported by the German ‘Förderprogramm Biotechnologie Baden-Württemberg’ projects 720.830-1-1/46b and 720.830-3-9, the German ‘Fortüne’ project 1862-0-0, the German ‘Deutsche Forschungsgemeinschaft Sonderforschungsbereich 685’ projects A6, C5 and C9, the German ‘Bundesministerium für Bildung und Forschung’ project 0315890F, the Italian ‘Fondazione Cassa di Risparmio di Verona, Vicenza, Belluno e Ancona’ and the Italian ‘Associazione Italiana Ricerca sul Cancro’ (grant 6599). We thank H. Schild for providing critical input to the manuscript and the members of the Immatics’ Scientific Advisory Board and the Data Safety Monitoring Board for critical input throughout the development program.

PY - 2012/8

Y1 - 2012/8

N2 - IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-Associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02 + subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3) + regulatory T (T reg) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T reg cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

AB - IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-Associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02 + subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3) + regulatory T (T reg) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T reg cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

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U2 - 10.1038/nm.2883

DO - 10.1038/nm.2883

M3 - Article

C2 - 22842478

AN - SCOPUS:84864662070

SN - 1078-8956

VL - 18

SP - 1254

EP - 1261

JO - Nature Medicine

JF - Nature Medicine

IS - 8

ER -

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

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