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

被引：610

作者：

Walter, Steffen ^{[1
]}

Weinschenk, Toni ^{[1
]}

Stenzl, Arnulf ^{[2
]}

Zdrojowy, Romuald ^{[3
]}

Pluzanska, Anna ^{[4
]}

Szczylik, Cezary ^{[5
]}

Staehler, Michael ^{[6
]}

Brugger, Wolfram ^{[7
,8
]}

Dietrich, Pierre-Yves ^{[9
]}

Mendrzyk, Regina ^{[1
]}

Hilf, Norbert ^{[1
]}

Schoor, Oliver ^{[1
]}

Fritsche, Jens ^{[1
]}

Mahr, Andrea ^{[1
]}

Maurer, Dominik ^{[1
]}

Vass, Verona ^{[1
]}

Trautwein, Claudia ^{[1
]}

Lewandrowski, Peter ^{[1
]}

Flohr, Christian ^{[1
]}

Pohla, Heike ^{[10
,11
]}

Stanczak, Janusz J. ^{[12
]}

Bronte, Vincenzo ^{[13
]}

Mandruzzato, Susanna ^{[14
,15
]}

Biedermann, Tilo ^{[16
]}

Pawelec, Graham ^{[17
]}

Derhovanessian, Evelyna ^{[17
]}

Yamagishi, Hisakazu ^{[18
]}

Miki, Tsuneharu ^{[19
]}

Hongo, Fumiya ^{[19
]}

Takaha, Natsuki ^{[19
]}

Hirakawa, Kosei ^{[20
]}

Tanaka, Hiroaki ^{[20
]}

Stevanovic, Stefan ^{[21
]}

Frisch, Juergen ^{[1
]}

Mayer-Mokler, Andrea ^{[1
]}

Kirner, Alexandra ^{[1
]}

Rammensee, Hans-Georg ^{[21
]}

Reinhardt, Carsten ^{[1
]}

Singh-Jasuja, Harpreet ^{[1
]}

机构：

[1] Immat Biotechnol GmbH, Tubingen, Germany

[2] Univ Tubingen, Dept Urol, Tubingen, Germany

[3] Univ Med, Dept Urol & Urol Oncol, Wroclaw, Poland

[4] Uniwersytetu Med, Klin Chemiotherapii Nowotworow UM, Lodz, Poland

[5] Mil Inst Med, Dept Oncol, Warsaw, Poland

[6] Univ Munich, IZN, Munich, Germany

[7] Univ Freiburg, Schwarzwald Baar Klinikum, Dept Hematol Oncol & Immunol, Villingen Schwenningen, Germany

[8] Univ Freiburg, Acad Teaching Hosp, Villingen Schwenningen, Germany

[9] Univ Hosp Geneva, Ctr Oncol, Lab Tumour Immunol, Geneva, Switzerland

[10] Univ Munich, LIFE Ctr, Lab Tumor Immunol, Munich, Germany

[11] Helmholtz Ctr, Inst Mol Immunol, Munich, Germany

[12] Hosp Infect Dis, Mol Diagnost Lab, Warsaw, Poland

[13] Verona Univ Hosp, Dept Pathol & Diagnost, Verona, Italy

[14] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy

[15] IRCCS, IOV, Padua, Italy

[16] Univ Tubingen, Dept Dermatol, Tubingen, Germany

[17] Univ Tubingen, Med Res Ctr, Dept Internal Med 2, Tubingen, Germany

[18] Kyoto Prefectural Univ Med, Dept Surg, Kyoto 602, Japan

[19] Kyoto Prefectural Univ Med, Dept Urol, Kyoto, Japan

[20] Osaka City Univ, Dept Surg Oncol, Osaka 558, Japan

[21] Univ Tubingen, Dept Immunol, Tubingen, Germany

来源：

NATURE MEDICINE | 2012年 / 18卷 / 08期

关键词：

REGULATORY T-CELLS; COLONY-STIMULATING FACTOR; MYELOID SUPPRESSOR-CELLS; DENDRITIC CELLS; TUMOR-ANTIGEN; MELANOMA PATIENTS; HIGH-FREQUENCIES; PEPTIDE VACCINE; CUTTING EDGE; IDENTIFICATION;

D O I：

10.1038/nm.2883

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1254 / +

页数：23

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