Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
Standard
Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. / Sahin, Ugur; Derhovanessian, Evelyna; Miller, Matthias; Kloke, Björn-Philipp; Simon, Petra; Löwer, Martin; Bukur, Valesca; Tadmor, Arbel D; Luxemburger, Ulrich; Schrörs, Barbara; Omokoko, Tana; Vormehr, Mathias; Albrecht, Christian; Paruzynski, Anna; Kuhn, Andreas N; Buck, Janina; Heesch, Sandra; Schreeb, Katharina H; Müller, Felicitas; Ortseifer, Inga; Vogler, Isabel; Godehardt, Eva; Attig, Sebastian; Rae, Richard; Breitkreuz, Andrea; Tolliver, Claudia; Suchan, Martin; Martic, Goran; Hohberger, Alexander; Sorn, Patrick; Diekmann, Jan; Ciesla, Janko; Waksmann, Olga; Brück, Alexandra-Kemmer; Witt, Meike; Zillgen, Martina; Rothermel, Andree; Kasemann, Barbara; Langer, David; Bolte, Stefanie; Diken, Mustafa; Kreiter, Sebastian; Nemecek, Romina; Gebhardt, Christoffer; Grabbe, Stephan; Höller, Christoph; Utikal, Jochen; Huber, Christoph; Loquai, Carmen; Türeci, Özlem.
In: NATURE, Vol. 547, No. 7662, 13.07.2017, p. 222-226.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
AU - Sahin, Ugur
AU - Derhovanessian, Evelyna
AU - Miller, Matthias
AU - Kloke, Björn-Philipp
AU - Simon, Petra
AU - Löwer, Martin
AU - Bukur, Valesca
AU - Tadmor, Arbel D
AU - Luxemburger, Ulrich
AU - Schrörs, Barbara
AU - Omokoko, Tana
AU - Vormehr, Mathias
AU - Albrecht, Christian
AU - Paruzynski, Anna
AU - Kuhn, Andreas N
AU - Buck, Janina
AU - Heesch, Sandra
AU - Schreeb, Katharina H
AU - Müller, Felicitas
AU - Ortseifer, Inga
AU - Vogler, Isabel
AU - Godehardt, Eva
AU - Attig, Sebastian
AU - Rae, Richard
AU - Breitkreuz, Andrea
AU - Tolliver, Claudia
AU - Suchan, Martin
AU - Martic, Goran
AU - Hohberger, Alexander
AU - Sorn, Patrick
AU - Diekmann, Jan
AU - Ciesla, Janko
AU - Waksmann, Olga
AU - Brück, Alexandra-Kemmer
AU - Witt, Meike
AU - Zillgen, Martina
AU - Rothermel, Andree
AU - Kasemann, Barbara
AU - Langer, David
AU - Bolte, Stefanie
AU - Diken, Mustafa
AU - Kreiter, Sebastian
AU - Nemecek, Romina
AU - Gebhardt, Christoffer
AU - Grabbe, Stephan
AU - Höller, Christoph
AU - Utikal, Jochen
AU - Huber, Christoph
AU - Loquai, Carmen
AU - Türeci, Özlem
PY - 2017/7/13
Y1 - 2017/7/13
N2 - T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
AB - T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.
KW - Antibodies, Monoclonal
KW - B7-H1 Antigen
KW - CD8 Antigens
KW - Cancer Vaccines
KW - Epitopes
KW - Humans
KW - Immunotherapy
KW - Melanoma
KW - Mutation
KW - Neoplasm Metastasis
KW - Neoplasm Recurrence, Local
KW - Precision Medicine
KW - Programmed Cell Death 1 Receptor
KW - RNA
KW - T-Lymphocytes
KW - Vaccination
KW - beta 2-Microglobulin
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/nature23003
DO - 10.1038/nature23003
M3 - SCORING: Journal article
C2 - 28678784
VL - 547
SP - 222
EP - 226
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 7662
ER -