Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma. Personalized cancer vaccine trials Neoantigens have long been considered optimal targets for anti-tumour vaccines, and recent mutation coding and prediction techniques have aimed to...
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| Veröffentlicht in: | Nature (London) Jg. 547; H. 7662; S. 222 - 226 |
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
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London
Nature Publishing Group UK
13.07.2017
Nature Publishing Group |
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| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
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| Abstract | The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma.
Personalized cancer vaccine trials
Neoantigens have long been considered optimal targets for anti-tumour vaccines, and recent mutation coding and prediction techniques have aimed to streamline their identification and selection. Two papers in this issue report results from personalized neoantigen vaccine trials in patients with cancer. Catherine Wu and colleagues report the results of a phase I trial of a personalized cancer vaccine that targets up to 20 patient neoantigens. The vaccine was safe and induced tumour-antigen-specific immune responses. Four out of six patients treated showed no recurrence at 25 months, and progressing patients responded to further therapy with checkpoint inhibitor. Ugur Sahin and colleagues report the first-in-human application of a personalized neoantigen vaccine in patients with melanoma. Their vaccination strategy includes sequencing and computational identification of neoantigens from patients, and design and manufacture of a poly-antigen RNA vaccine for treatment. In 13 patients, the vaccine boosted immunity against some of the selected tumour antigens from the individual patients, and two patients showed infiltration of tumour-reactive T cells. These results suggest that personalized vaccines could be refined and tailored to provide clinical benefit as cancer immunotherapies.
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
1
,
2
. 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. |
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| AbstractList | 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.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. 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. The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma. Personalized cancer vaccine trials Neoantigens have long been considered optimal targets for anti-tumour vaccines, and recent mutation coding and prediction techniques have aimed to streamline their identification and selection. Two papers in this issue report results from personalized neoantigen vaccine trials in patients with cancer. Catherine Wu and colleagues report the results of a phase I trial of a personalized cancer vaccine that targets up to 20 patient neoantigens. The vaccine was safe and induced tumour-antigen-specific immune responses. Four out of six patients treated showed no recurrence at 25 months, and progressing patients responded to further therapy with checkpoint inhibitor. Ugur Sahin and colleagues report the first-in-human application of a personalized neoantigen vaccine in patients with melanoma. Their vaccination strategy includes sequencing and computational identification of neoantigens from patients, and design and manufacture of a poly-antigen RNA vaccine for treatment. In 13 patients, the vaccine boosted immunity against some of the selected tumour antigens from the individual patients, and two patients showed infiltration of tumour-reactive T cells. These results suggest that personalized vaccines could be refined and tailored to provide clinical benefit as cancer immunotherapies. 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 1 , 2 . 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. 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 mutations1,2. 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 ß2-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. |
| Audience | Academic |
| Author | Höller, Christoph Paruzynski, Anna Utikal, Jochen Miller, Matthias Buck, Janina Huber, Christoph Kloke, Björn-Philipp Brück, Alexandra-Kemmer Ortseifer, Inga Kuhn, Andreas N. Ciesla, Janko Langer, David Omokoko, Tana Rae, Richard Nemecek, Romina Diekmann, Jan Schrörs, Barbara Hohberger, Alexander Gebhardt, Christoffer Türeci, Özlem Bukur, Valesca Albrecht, Christian Heesch, Sandra Simon, Petra Breitkreuz, Andrea Vogler, Isabel Tolliver, Claudia Löwer, Martin Kreiter, Sebastian Bolte, Stefanie Derhovanessian, Evelyna Waksmann, Olga Rothermel, Andree Martic, Goran Kasemann, Barbara Sorn, Patrick Witt, Meike Loquai, Carmen Vormehr, Mathias Godehardt, Eva Grabbe, Stephan Müller, Felicitas Suchan, Martin Sahin, Ugur Attig, Sebastian Schreeb, Katharina H. Luxemburger, Ulrich Tadmor, Arbel D. Diken, Mustafa Zillgen, Martina |
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Löwer fullname: Löwer, Martin organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 7 givenname: Valesca surname: Bukur fullname: Bukur, Valesca organization: Biopharmaceutical New Technologies (BioNTech) Corporation, TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 8 givenname: Arbel D. surname: Tadmor fullname: Tadmor, Arbel D. organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 9 givenname: Ulrich surname: Luxemburger fullname: Luxemburger, Ulrich organization: Biopharmaceutical New Technologies (BioNTech) Corporation – sequence: 10 givenname: Barbara surname: Schrörs fullname: Schrörs, Barbara organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 11 givenname: Tana surname: Omokoko fullname: 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Johannes Gutenberg University gGmbH, University Medical Center of the Johannes Gutenberg University – sequence: 24 givenname: Richard surname: Rae fullname: Rae, Richard organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 25 givenname: Andrea surname: Breitkreuz fullname: Breitkreuz, Andrea organization: Biopharmaceutical New Technologies (BioNTech) Corporation – sequence: 26 givenname: Claudia surname: Tolliver fullname: Tolliver, Claudia organization: Biopharmaceutical New Technologies (BioNTech) Corporation – sequence: 27 givenname: Martin surname: Suchan fullname: Suchan, Martin organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 28 givenname: Goran surname: Martic fullname: Martic, Goran organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 29 givenname: 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Martina surname: Zillgen fullname: Zillgen, Martina organization: Biopharmaceutical New Technologies (BioNTech) Corporation – sequence: 37 givenname: Andree surname: Rothermel fullname: Rothermel, Andree organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 38 givenname: Barbara surname: Kasemann fullname: Kasemann, Barbara organization: TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 39 givenname: David surname: Langer fullname: Langer, David organization: Biopharmaceutical New Technologies (BioNTech) Corporation – sequence: 40 givenname: Stefanie surname: Bolte fullname: Bolte, Stefanie organization: Biopharmaceutical New Technologies (BioNTech) Corporation – sequence: 41 givenname: Mustafa surname: Diken fullname: Diken, Mustafa organization: Biopharmaceutical New Technologies (BioNTech) Corporation, TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 42 givenname: Sebastian surname: Kreiter fullname: Kreiter, Sebastian organization: Biopharmaceutical New Technologies (BioNTech) Corporation, TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH – sequence: 43 givenname: Romina surname: Nemecek fullname: Nemecek, Romina organization: Medical University of Vienna – sequence: 44 givenname: Christoffer surname: Gebhardt fullname: Gebhardt, Christoffer organization: German Cancer Research Center (DKFZ), University Medical Center Mannheim, Heidelberg University – sequence: 45 givenname: Stephan surname: Grabbe fullname: Grabbe, Stephan organization: University Medical Center of the Johannes Gutenberg University – sequence: 46 givenname: Christoph surname: Höller fullname: Höller, Christoph organization: Medical University of Vienna – sequence: 47 givenname: Jochen surname: Utikal fullname: Utikal, Jochen organization: German Cancer Research Center (DKFZ), University Medical Center Mannheim, Heidelberg University – sequence: 48 givenname: Christoph surname: Huber fullname: Huber, Christoph organization: Biopharmaceutical New Technologies (BioNTech) Corporation, TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, University Medical Center of the Johannes Gutenberg University – sequence: 49 givenname: Carmen surname: Loquai fullname: Loquai, Carmen organization: University Medical Center of the Johannes Gutenberg University – sequence: 50 givenname: Özlem surname: Türeci fullname: Türeci, Özlem organization: CI3 - Cluster for Individualized Immunointervention e.V |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28678784$$D View this record in MEDLINE/PubMed |
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| Copyright | Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 2017 COPYRIGHT 2017 Nature Publishing Group Copyright Nature Publishing Group Jul 13, 2017 |
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| Snippet | The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma.
Personalized cancer vaccine trials... T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced... |
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| Title | Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer |
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