Actively personalized vaccination trial for newly diagnosed glioblastoma

Norbert Hilf; Sabrina Kuttruff-Coqui; Katrin Frenzel; Valesca Bukur; Stefan Stevanović; Cécile Gouttefangeas; Michael Platten; Ghazaleh Tabatabai; Valerie Dutoit; Sjoerd H. van der Burg; Per thor Straten; Francisco Martínez-Ricarte; Berta Ponsati; Hideho Okada; Ulrik Lassen; Arie Admon; Christian H. Ottensmeier; Alexander Ulges; Sebastian Kreiter; Andreas von Deimling; Marco Skardelly; Denis Migliorini; Judith R. Kroep; Manja Idorn; Jordi Rodon; Jordi Piró; Hans S. Poulsen; Bracha Shraibman; Katy McCann; Regina Mendrzyk; Martin Löwer; Monika Stieglbauer; Cedrik M. Britten; David Capper; Marij J.P. Welters; Juan Sahuquillo; Katharina Kiesel; Evelyna Derhovanessian; Elisa Rusch; Lukas Bunse; Colette Song; Sandra Heesch; Claudia Wagner; Alexandra Kemmer-Brück; Jörg Ludwig; John C. Castle; Oliver Schoor; Arbel D. Tadmor; Edward Green; Jens Fritsche; Miriam Meyer; Nina Pawlowski; Sonja Dorner; Franziska Hoffgaard; Bernhard Rössler; Dominik Maurer; Toni Weinschenk; Carsten Reinhardt; Christoph Huber; Hans Georg Rammensee; Harpreet Singh-Jasuja; Ugur Sahin; Pierre Yves Dietrich; Wolfgang Wick

doi:10.1038/s41586-018-0810-y

Actively personalized vaccination trial for newly diagnosed glioblastoma

Norbert Hilf, Sabrina Kuttruff-Coqui, Katrin Frenzel, Valesca Bukur, Stefan Stevanović, Cécile Gouttefangeas, Michael Platten, Ghazaleh Tabatabai, Valerie Dutoit, Sjoerd H. van der Burg, Per thor Straten, Francisco Martínez-Ricarte, Berta Ponsati, Hideho Okada, Ulrik Lassen, Arie Admon, Christian H. Ottensmeier, Alexander Ulges, Sebastian Kreiter, Andreas von DeimlingMarco Skardelly, Denis Migliorini, Judith R. Kroep, Manja Idorn, Jordi Rodon, Jordi Piró, Hans S. Poulsen, Bracha Shraibman, Katy McCann, Regina Mendrzyk, Martin Löwer, Monika Stieglbauer, Cedrik M. Britten, David Capper, Marij J.P. Welters, Juan Sahuquillo, Katharina Kiesel, Evelyna Derhovanessian, Elisa Rusch, Lukas Bunse, Colette Song, Sandra Heesch, Claudia Wagner, Alexandra Kemmer-Brück, Jörg Ludwig, John C. Castle, Oliver Schoor, Arbel D. Tadmor, Edward Green, Jens Fritsche, Miriam Meyer, Nina Pawlowski, Sonja Dorner, Franziska Hoffgaard, Bernhard Rössler, Dominik Maurer, Toni Weinschenk, Carsten Reinhardt, Christoph Huber, Hans Georg Rammensee, Harpreet Singh-Jasuja, Ugur Sahin, Pierre Yves Dietrich, Wolfgang Wick^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

238 Citationer (Scopus)

Abstract

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors^1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential³. There is limited intratumoural infiltration of immune cells⁴ in glioblastoma and these tumours contain only 30–50 non-synonymous mutations⁵. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8⁺ T cells. APVAC2 induced predominantly CD4⁺ T cell responses of T helper 1 type against predicted neoepitopes.

Originalsprog	Engelsk
Tidsskrift	Nature
Vol/bind	565
Udgave nummer	7738
Sider (fra-til)	240-245
Antal sider	6
ISSN	0028-0836
DOI	https://doi.org/10.1038/s41586-018-0810-y
Status	Udgivet - 2019

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Correction to: Nature https://doi.org/10.1038/s41586-018-0810-y, published online 19 December 2018. In this Letter, owing to an error in the production process, the additional author support information was omitted from the Supplementary Information. The Supplementary Information of the original Letter has been corrected online.

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Hilf, N., Kuttruff-Coqui, S., Frenzel, K., Bukur, V., Stevanović, S., Gouttefangeas, C., Platten, M., Tabatabai, G., Dutoit, V., van der Burg, S. H., thor Straten, P., Martínez-Ricarte, F., Ponsati, B., Okada, H., Lassen, U., Admon, A., Ottensmeier, C. H., Ulges, A., Kreiter, S., ... Wick, W. (2019). Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature, 565(7738), 240-245. https://doi.org/10.1038/s41586-018-0810-y

Hilf, N, Kuttruff-Coqui, S, Frenzel, K, Bukur, V, Stevanović, S, Gouttefangeas, C, Platten, M, Tabatabai, G, Dutoit, V, van der Burg, SH, thor Straten, P, Martínez-Ricarte, F, Ponsati, B, Okada, H, Lassen, U, Admon, A, Ottensmeier, CH, Ulges, A, Kreiter, S, von Deimling, A, Skardelly, M, Migliorini, D, Kroep, JR, Idorn, M, Rodon, J, Piró, J, Poulsen, HS, Shraibman, B, McCann, K, Mendrzyk, R, Löwer, M, Stieglbauer, M, Britten, CM, Capper, D, Welters, MJP, Sahuquillo, J, Kiesel, K, Derhovanessian, E, Rusch, E, Bunse, L, Song, C, Heesch, S, Wagner, C, Kemmer-Brück, A, Ludwig, J, Castle, JC, Schoor, O, Tadmor, AD, Green, E, Fritsche, J, Meyer, M, Pawlowski, N, Dorner, S, Hoffgaard, F, Rössler, B, Maurer, D, Weinschenk, T, Reinhardt, C, Huber, C, Rammensee, HG, Singh-Jasuja, H, Sahin, U, Dietrich, PY & Wick, W 2019, 'Actively personalized vaccination trial for newly diagnosed glioblastoma', Nature, bind 565, nr. 7738, s. 240-245. https://doi.org/10.1038/s41586-018-0810-y

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title = "Actively personalized vaccination trial for newly diagnosed glioblastoma",

abstract = "Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.",

author = "Norbert Hilf and Sabrina Kuttruff-Coqui and Katrin Frenzel and Valesca Bukur and Stefan Stevanovi{\'c} and C{\'e}cile Gouttefangeas and Michael Platten and Ghazaleh Tabatabai and Valerie Dutoit and {van der Burg}, {Sjoerd H.} and {thor Straten}, Per and Francisco Mart{\'i}nez-Ricarte and Berta Ponsati and Hideho Okada and Ulrik Lassen and Arie Admon and Ottensmeier, {Christian H.} and Alexander Ulges and Sebastian Kreiter and {von Deimling}, Andreas and Marco Skardelly and Denis Migliorini and Kroep, {Judith R.} and Manja Idorn and Jordi Rodon and Jordi Pir{\'o} and Poulsen, {Hans S.} and Bracha Shraibman and Katy McCann and Regina Mendrzyk and Martin L{\"o}wer and Monika Stieglbauer and Britten, {Cedrik M.} and David Capper and Welters, {Marij J.P.} and Juan Sahuquillo and Katharina Kiesel and Evelyna Derhovanessian and Elisa Rusch and Lukas Bunse and Colette Song and Sandra Heesch and Claudia Wagner and Alexandra Kemmer-Br{\"u}ck and J{\"o}rg Ludwig and Castle, {John C.} and Oliver Schoor and Tadmor, {Arbel D.} and Edward Green and Jens Fritsche and Miriam Meyer and Nina Pawlowski and Sonja Dorner and Franziska Hoffgaard and Bernhard R{\"o}ssler and Dominik Maurer and Toni Weinschenk and Carsten Reinhardt and Christoph Huber and Rammensee, {Hans Georg} and Harpreet Singh-Jasuja and Ugur Sahin and Dietrich, {Pierre Yves} and Wolfgang Wick",

year = "2019",

doi = "10.1038/s41586-018-0810-y",

language = "English",

volume = "565",

pages = "240--245",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

number = "7738",

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TY - JOUR

T1 - Actively personalized vaccination trial for newly diagnosed glioblastoma

AU - Hilf, Norbert

AU - Kuttruff-Coqui, Sabrina

AU - Frenzel, Katrin

AU - Bukur, Valesca

AU - Stevanović, Stefan

AU - Gouttefangeas, Cécile

AU - Platten, Michael

AU - Tabatabai, Ghazaleh

AU - Dutoit, Valerie

AU - van der Burg, Sjoerd H.

AU - thor Straten, Per

AU - Martínez-Ricarte, Francisco

AU - Ponsati, Berta

AU - Okada, Hideho

AU - Lassen, Ulrik

AU - Admon, Arie

AU - Ottensmeier, Christian H.

AU - Ulges, Alexander

AU - Kreiter, Sebastian

AU - von Deimling, Andreas

AU - Skardelly, Marco

AU - Migliorini, Denis

AU - Kroep, Judith R.

AU - Idorn, Manja

AU - Rodon, Jordi

AU - Piró, Jordi

AU - Poulsen, Hans S.

AU - Shraibman, Bracha

AU - McCann, Katy

AU - Mendrzyk, Regina

AU - Löwer, Martin

AU - Stieglbauer, Monika

AU - Britten, Cedrik M.

AU - Capper, David

AU - Welters, Marij J.P.

AU - Sahuquillo, Juan

AU - Kiesel, Katharina

AU - Derhovanessian, Evelyna

AU - Rusch, Elisa

AU - Bunse, Lukas

AU - Song, Colette

AU - Heesch, Sandra

AU - Wagner, Claudia

AU - Kemmer-Brück, Alexandra

AU - Ludwig, Jörg

AU - Castle, John C.

AU - Schoor, Oliver

AU - Tadmor, Arbel D.

AU - Green, Edward

AU - Fritsche, Jens

AU - Meyer, Miriam

AU - Pawlowski, Nina

AU - Dorner, Sonja

AU - Hoffgaard, Franziska

AU - Rössler, Bernhard

AU - Maurer, Dominik

AU - Weinschenk, Toni

AU - Reinhardt, Carsten

AU - Huber, Christoph

AU - Rammensee, Hans Georg

AU - Singh-Jasuja, Harpreet

AU - Sahin, Ugur

AU - Dietrich, Pierre Yves

AU - Wick, Wolfgang

PY - 2019

Y1 - 2019

N2 - Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.

AB - Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.

UR - https://www.nature.com/articles/s41586-019-0959-z

U2 - 10.1038/s41586-018-0810-y

DO - 10.1038/s41586-018-0810-y

M3 - Letter

C2 - 30568303

AN - SCOPUS:85059762738

SN - 0028-0836

VL - 565

SP - 240

EP - 245

JO - Nature

JF - Nature

IS - 7738

ER -

Actively personalized vaccination trial for newly diagnosed glioblastoma

Abstract

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