An immunogenic personal neoantigen vaccine for patients with melanoma
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thym...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ott, Patrick A [verfasserIn] |
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| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Nature - London : Macmillan Publishers Limited, part of Springer Nature, 1869, 547(2017), 7662, Seite 217 |
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| Übergeordnetes Werk: |
volume:547 ; year:2017 ; number:7662 ; pages:217 |
| Links: |
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| DOI / URN: |
10.1038/nature22991 |
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| Katalog-ID: |
OLC1996022628 |
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| 245 | 1 | 3 | |a An immunogenic personal neoantigen vaccine for patients with melanoma |
| 264 | 1 | |c 2017 | |
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| 520 | |a Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. | ||
| 650 | 4 | |a Melanoma | |
| 650 | 4 | |a Tumor antigens | |
| 650 | 4 | |a Vaccines | |
| 650 | 4 | |a Feasibility studies | |
| 650 | 4 | |a Histocompatibility antigen HLA | |
| 650 | 4 | |a Tissues | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Feasibility analysis | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Lymphocytes | |
| 650 | 4 | |a Gene expression | |
| 650 | 4 | |a CD4 antigen | |
| 650 | 4 | |a Antigens | |
| 650 | 4 | |a Lymphocytes T | |
| 650 | 4 | |a Mutations | |
| 650 | 4 | |a Thymus | |
| 650 | 4 | |a Patients | |
| 650 | 4 | |a Studies | |
| 650 | 4 | |a CD8 antigen | |
| 650 | 4 | |a Tumors | |
| 650 | 4 | |a Immunity | |
| 650 | 4 | |a Immunological tolerance | |
| 650 | 4 | |a Vaccination | |
| 650 | 4 | |a PD-1 protein | |
| 650 | 4 | |a Cell death | |
| 650 | 4 | |a Immunogenicity | |
| 650 | 4 | |a Peptides | |
| 650 | 4 | |a Mutation | |
| 650 | 4 | |a T cell receptors | |
| 700 | 1 | |a Hu, Zhuting |4 oth | |
| 700 | 1 | |a Keskin, Derin B |4 oth | |
| 700 | 1 | |a Shukla, Sachet A |4 oth | |
| 700 | 1 | |a Sun, Jing |4 oth | |
| 700 | 1 | |a Bozym, David J |4 oth | |
| 700 | 1 | |a Zhang, Wandi |4 oth | |
| 700 | 1 | |a Luoma, Adrienne |4 oth | |
| 700 | 1 | |a Giobbie-Hurder, Anita |4 oth | |
| 700 | 1 | |a Peter, Lauren |4 oth | |
| 700 | 1 | |a Chen, Christina |4 oth | |
| 700 | 1 | |a Olive, Oriol |4 oth | |
| 700 | 1 | |a Carter, Todd A |4 oth | |
| 700 | 1 | |a Li, Shuqiang |4 oth | |
| 700 | 1 | |a Lieb, David J |4 oth | |
| 700 | 1 | |a Eisenhaure, Thomas |4 oth | |
| 700 | 1 | |a Gjini, Evisa |4 oth | |
| 700 | 1 | |a Stevens, Jonathan |4 oth | |
| 700 | 1 | |a Lane, William J |4 oth | |
| 700 | 1 | |a Javeri, Indu |4 oth | |
| 700 | 1 | |a Nellaiappan, Kaliappanadar |4 oth | |
| 700 | 1 | |a Salazar, Andres M |4 oth | |
| 700 | 1 | |a Daley, Heather |4 oth | |
| 700 | 1 | |a Seaman, Michael |4 oth | |
| 700 | 1 | |a Buchbinder, Elizabeth I |4 oth | |
| 700 | 1 | |a Yoon, Charles H |4 oth | |
| 700 | 1 | |a Harden, Maegan |4 oth | |
| 700 | 1 | |a Lennon, Niall |4 oth | |
| 700 | 1 | |a Gabriel, Stacey |4 oth | |
| 700 | 1 | |a Rodig, Scott J |4 oth | |
| 700 | 1 | |a Barouch, Dan H |4 oth | |
| 700 | 1 | |a Aster, Jon C |4 oth | |
| 700 | 1 | |a Getz, Gad |4 oth | |
| 700 | 1 | |a Wucherpfennig, Kai |4 oth | |
| 700 | 1 | |a Neuberg, Donna |4 oth | |
| 700 | 1 | |a Ritz, Jerome |4 oth | |
| 700 | 1 | |a Lander, Eric S |4 oth | |
| 700 | 1 | |a Fritsch, Edward F |4 oth | |
| 700 | 1 | |a Hacohen, Nir |4 oth | |
| 700 | 1 | |a Wu, Catherine J |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t Nature |d London : Macmillan Publishers Limited, part of Springer Nature, 1869 |g 547(2017), 7662, Seite 217 |w (DE-627)129292834 |w (DE-600)120714-3 |w (DE-576)014473941 |x 0028-0836 |7 nnns |
| 773 | 1 | 8 | |g volume:547 |g year:2017 |g number:7662 |g pages:217 |
| 856 | 4 | 1 | |u http://dx.doi.org/10.1038/nature22991 |3 Volltext |
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10.1038/nature22991 doi PQ20170901 (DE-627)OLC1996022628 (DE-599)GBVOLC1996022628 (PRQ)g1469-1af14d4915f7f2500bdbe0a9a37ddb3c3c02b906c77ee3e28ac3509fdef6bb180 (KEY)0072945020170000547766200217immunogenicpersonalneoantigenvaccineforpatientswit DE-627 ger DE-627 rakwb eng 070 500 DE-101 500 AVZ BIODIV fid Ott, Patrick A verfasserin aut An immunogenic personal neoantigen vaccine for patients with melanoma 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. Melanoma Tumor antigens Vaccines Feasibility studies Histocompatibility antigen HLA Tissues Apoptosis Feasibility analysis Immunotherapy Lymphocytes Gene expression CD4 antigen Antigens Lymphocytes T Mutations Thymus Patients Studies CD8 antigen Tumors Immunity Immunological tolerance Vaccination PD-1 protein Cell death Immunogenicity Peptides Mutation T cell receptors Hu, Zhuting oth Keskin, Derin B oth Shukla, Sachet A oth Sun, Jing oth Bozym, David J oth Zhang, Wandi oth Luoma, Adrienne oth Giobbie-Hurder, Anita oth Peter, Lauren oth Chen, Christina oth Olive, Oriol oth Carter, Todd A oth Li, Shuqiang oth Lieb, David J oth Eisenhaure, Thomas oth Gjini, Evisa oth Stevens, Jonathan oth Lane, William J oth Javeri, Indu oth Nellaiappan, Kaliappanadar oth Salazar, Andres M oth Daley, Heather oth Seaman, Michael oth Buchbinder, Elizabeth I oth Yoon, Charles H oth Harden, Maegan oth Lennon, Niall oth Gabriel, Stacey oth Rodig, Scott J oth Barouch, Dan H oth Aster, Jon C oth Getz, Gad oth Wucherpfennig, Kai oth Neuberg, Donna oth Ritz, Jerome oth Lander, Eric S oth Fritsch, Edward F oth Hacohen, Nir oth Wu, Catherine J oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 547(2017), 7662, Seite 217 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:547 year:2017 number:7662 pages:217 http://dx.doi.org/10.1038/nature22991 Volltext https://search.proquest.com/docview/1920222004 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_135 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_252 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 AR 547 2017 7662 217 |
| spelling |
10.1038/nature22991 doi PQ20170901 (DE-627)OLC1996022628 (DE-599)GBVOLC1996022628 (PRQ)g1469-1af14d4915f7f2500bdbe0a9a37ddb3c3c02b906c77ee3e28ac3509fdef6bb180 (KEY)0072945020170000547766200217immunogenicpersonalneoantigenvaccineforpatientswit DE-627 ger DE-627 rakwb eng 070 500 DE-101 500 AVZ BIODIV fid Ott, Patrick A verfasserin aut An immunogenic personal neoantigen vaccine for patients with melanoma 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. Melanoma Tumor antigens Vaccines Feasibility studies Histocompatibility antigen HLA Tissues Apoptosis Feasibility analysis Immunotherapy Lymphocytes Gene expression CD4 antigen Antigens Lymphocytes T Mutations Thymus Patients Studies CD8 antigen Tumors Immunity Immunological tolerance Vaccination PD-1 protein Cell death Immunogenicity Peptides Mutation T cell receptors Hu, Zhuting oth Keskin, Derin B oth Shukla, Sachet A oth Sun, Jing oth Bozym, David J oth Zhang, Wandi oth Luoma, Adrienne oth Giobbie-Hurder, Anita oth Peter, Lauren oth Chen, Christina oth Olive, Oriol oth Carter, Todd A oth Li, Shuqiang oth Lieb, David J oth Eisenhaure, Thomas oth Gjini, Evisa oth Stevens, Jonathan oth Lane, William J oth Javeri, Indu oth Nellaiappan, Kaliappanadar oth Salazar, Andres M oth Daley, Heather oth Seaman, Michael oth Buchbinder, Elizabeth I oth Yoon, Charles H oth Harden, Maegan oth Lennon, Niall oth Gabriel, Stacey oth Rodig, Scott J oth Barouch, Dan H oth Aster, Jon C oth Getz, Gad oth Wucherpfennig, Kai oth Neuberg, Donna oth Ritz, Jerome oth Lander, Eric S oth Fritsch, Edward F oth Hacohen, Nir oth Wu, Catherine J oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 547(2017), 7662, Seite 217 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:547 year:2017 number:7662 pages:217 http://dx.doi.org/10.1038/nature22991 Volltext https://search.proquest.com/docview/1920222004 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_135 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_252 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 AR 547 2017 7662 217 |
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10.1038/nature22991 doi PQ20170901 (DE-627)OLC1996022628 (DE-599)GBVOLC1996022628 (PRQ)g1469-1af14d4915f7f2500bdbe0a9a37ddb3c3c02b906c77ee3e28ac3509fdef6bb180 (KEY)0072945020170000547766200217immunogenicpersonalneoantigenvaccineforpatientswit DE-627 ger DE-627 rakwb eng 070 500 DE-101 500 AVZ BIODIV fid Ott, Patrick A verfasserin aut An immunogenic personal neoantigen vaccine for patients with melanoma 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. Melanoma Tumor antigens Vaccines Feasibility studies Histocompatibility antigen HLA Tissues Apoptosis Feasibility analysis Immunotherapy Lymphocytes Gene expression CD4 antigen Antigens Lymphocytes T Mutations Thymus Patients Studies CD8 antigen Tumors Immunity Immunological tolerance Vaccination PD-1 protein Cell death Immunogenicity Peptides Mutation T cell receptors Hu, Zhuting oth Keskin, Derin B oth Shukla, Sachet A oth Sun, Jing oth Bozym, David J oth Zhang, Wandi oth Luoma, Adrienne oth Giobbie-Hurder, Anita oth Peter, Lauren oth Chen, Christina oth Olive, Oriol oth Carter, Todd A oth Li, Shuqiang oth Lieb, David J oth Eisenhaure, Thomas oth Gjini, Evisa oth Stevens, Jonathan oth Lane, William J oth Javeri, Indu oth Nellaiappan, Kaliappanadar oth Salazar, Andres M oth Daley, Heather oth Seaman, Michael oth Buchbinder, Elizabeth I oth Yoon, Charles H oth Harden, Maegan oth Lennon, Niall oth Gabriel, Stacey oth Rodig, Scott J oth Barouch, Dan H oth Aster, Jon C oth Getz, Gad oth Wucherpfennig, Kai oth Neuberg, Donna oth Ritz, Jerome oth Lander, Eric S oth Fritsch, Edward F oth Hacohen, Nir oth Wu, Catherine J oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 547(2017), 7662, Seite 217 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:547 year:2017 number:7662 pages:217 http://dx.doi.org/10.1038/nature22991 Volltext https://search.proquest.com/docview/1920222004 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_135 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_252 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 AR 547 2017 7662 217 |
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10.1038/nature22991 doi PQ20170901 (DE-627)OLC1996022628 (DE-599)GBVOLC1996022628 (PRQ)g1469-1af14d4915f7f2500bdbe0a9a37ddb3c3c02b906c77ee3e28ac3509fdef6bb180 (KEY)0072945020170000547766200217immunogenicpersonalneoantigenvaccineforpatientswit DE-627 ger DE-627 rakwb eng 070 500 DE-101 500 AVZ BIODIV fid Ott, Patrick A verfasserin aut An immunogenic personal neoantigen vaccine for patients with melanoma 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. Melanoma Tumor antigens Vaccines Feasibility studies Histocompatibility antigen HLA Tissues Apoptosis Feasibility analysis Immunotherapy Lymphocytes Gene expression CD4 antigen Antigens Lymphocytes T Mutations Thymus Patients Studies CD8 antigen Tumors Immunity Immunological tolerance Vaccination PD-1 protein Cell death Immunogenicity Peptides Mutation T cell receptors Hu, Zhuting oth Keskin, Derin B oth Shukla, Sachet A oth Sun, Jing oth Bozym, David J oth Zhang, Wandi oth Luoma, Adrienne oth Giobbie-Hurder, Anita oth Peter, Lauren oth Chen, Christina oth Olive, Oriol oth Carter, Todd A oth Li, Shuqiang oth Lieb, David J oth Eisenhaure, Thomas oth Gjini, Evisa oth Stevens, Jonathan oth Lane, William J oth Javeri, Indu oth Nellaiappan, Kaliappanadar oth Salazar, Andres M oth Daley, Heather oth Seaman, Michael oth Buchbinder, Elizabeth I oth Yoon, Charles H oth Harden, Maegan oth Lennon, Niall oth Gabriel, Stacey oth Rodig, Scott J oth Barouch, Dan H oth Aster, Jon C oth Getz, Gad oth Wucherpfennig, Kai oth Neuberg, Donna oth Ritz, Jerome oth Lander, Eric S oth Fritsch, Edward F oth Hacohen, Nir oth Wu, Catherine J oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 547(2017), 7662, Seite 217 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:547 year:2017 number:7662 pages:217 http://dx.doi.org/10.1038/nature22991 Volltext https://search.proquest.com/docview/1920222004 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_135 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_252 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 AR 547 2017 7662 217 |
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10.1038/nature22991 doi PQ20170901 (DE-627)OLC1996022628 (DE-599)GBVOLC1996022628 (PRQ)g1469-1af14d4915f7f2500bdbe0a9a37ddb3c3c02b906c77ee3e28ac3509fdef6bb180 (KEY)0072945020170000547766200217immunogenicpersonalneoantigenvaccineforpatientswit DE-627 ger DE-627 rakwb eng 070 500 DE-101 500 AVZ BIODIV fid Ott, Patrick A verfasserin aut An immunogenic personal neoantigen vaccine for patients with melanoma 2017 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. Melanoma Tumor antigens Vaccines Feasibility studies Histocompatibility antigen HLA Tissues Apoptosis Feasibility analysis Immunotherapy Lymphocytes Gene expression CD4 antigen Antigens Lymphocytes T Mutations Thymus Patients Studies CD8 antigen Tumors Immunity Immunological tolerance Vaccination PD-1 protein Cell death Immunogenicity Peptides Mutation T cell receptors Hu, Zhuting oth Keskin, Derin B oth Shukla, Sachet A oth Sun, Jing oth Bozym, David J oth Zhang, Wandi oth Luoma, Adrienne oth Giobbie-Hurder, Anita oth Peter, Lauren oth Chen, Christina oth Olive, Oriol oth Carter, Todd A oth Li, Shuqiang oth Lieb, David J oth Eisenhaure, Thomas oth Gjini, Evisa oth Stevens, Jonathan oth Lane, William J oth Javeri, Indu oth Nellaiappan, Kaliappanadar oth Salazar, Andres M oth Daley, Heather oth Seaman, Michael oth Buchbinder, Elizabeth I oth Yoon, Charles H oth Harden, Maegan oth Lennon, Niall oth Gabriel, Stacey oth Rodig, Scott J oth Barouch, Dan H oth Aster, Jon C oth Getz, Gad oth Wucherpfennig, Kai oth Neuberg, Donna oth Ritz, Jerome oth Lander, Eric S oth Fritsch, Edward F oth Hacohen, Nir oth Wu, Catherine J oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 547(2017), 7662, Seite 217 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:547 year:2017 number:7662 pages:217 http://dx.doi.org/10.1038/nature22991 Volltext https://search.proquest.com/docview/1920222004 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_22 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_135 GBV_ILN_154 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_252 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 AR 547 2017 7662 217 |
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Melanoma Tumor antigens Vaccines Feasibility studies Histocompatibility antigen HLA Tissues Apoptosis Feasibility analysis Immunotherapy Lymphocytes Gene expression CD4 antigen Antigens Lymphocytes T Mutations Thymus Patients Studies CD8 antigen Tumors Immunity Immunological tolerance Vaccination PD-1 protein Cell death Immunogenicity Peptides Mutation T cell receptors |
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Ott, Patrick A @@aut@@ Hu, Zhuting @@oth@@ Keskin, Derin B @@oth@@ Shukla, Sachet A @@oth@@ Sun, Jing @@oth@@ Bozym, David J @@oth@@ Zhang, Wandi @@oth@@ Luoma, Adrienne @@oth@@ Giobbie-Hurder, Anita @@oth@@ Peter, Lauren @@oth@@ Chen, Christina @@oth@@ Olive, Oriol @@oth@@ Carter, Todd A @@oth@@ Li, Shuqiang @@oth@@ Lieb, David J @@oth@@ Eisenhaure, Thomas @@oth@@ Gjini, Evisa @@oth@@ Stevens, Jonathan @@oth@@ Lane, William J @@oth@@ Javeri, Indu @@oth@@ Nellaiappan, Kaliappanadar @@oth@@ Salazar, Andres M @@oth@@ Daley, Heather @@oth@@ Seaman, Michael @@oth@@ Buchbinder, Elizabeth I @@oth@@ Yoon, Charles H @@oth@@ Harden, Maegan @@oth@@ Lennon, Niall @@oth@@ Gabriel, Stacey @@oth@@ Rodig, Scott J @@oth@@ Barouch, Dan H @@oth@@ Aster, Jon C @@oth@@ Getz, Gad @@oth@@ Wucherpfennig, Kai @@oth@@ Neuberg, Donna @@oth@@ Ritz, Jerome @@oth@@ Lander, Eric S @@oth@@ Fritsch, Edward F @@oth@@ Hacohen, Nir @@oth@@ Wu, Catherine J @@oth@@ |
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They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. 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|
| author |
Ott, Patrick A |
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Ott, Patrick A ddc 070 ddc 500 fid BIODIV misc Melanoma misc Tumor antigens misc Vaccines misc Feasibility studies misc Histocompatibility antigen HLA misc Tissues misc Apoptosis misc Feasibility analysis misc Immunotherapy misc Lymphocytes misc Gene expression misc CD4 antigen misc Antigens misc Lymphocytes T misc Mutations misc Thymus misc Patients misc Studies misc CD8 antigen misc Tumors misc Immunity misc Immunological tolerance misc Vaccination misc PD-1 protein misc Cell death misc Immunogenicity misc Peptides misc Mutation misc T cell receptors An immunogenic personal neoantigen vaccine for patients with melanoma |
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070 500 DE-101 500 AVZ BIODIV fid An immunogenic personal neoantigen vaccine for patients with melanoma Melanoma Tumor antigens Vaccines Feasibility studies Histocompatibility antigen HLA Tissues Apoptosis Feasibility analysis Immunotherapy Lymphocytes Gene expression CD4 antigen Antigens Lymphocytes T Mutations Thymus Patients Studies CD8 antigen Tumors Immunity Immunological tolerance Vaccination PD-1 protein Cell death Immunogenicity Peptides Mutation T cell receptors |
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ddc 070 ddc 500 fid BIODIV misc Melanoma misc Tumor antigens misc Vaccines misc Feasibility studies misc Histocompatibility antigen HLA misc Tissues misc Apoptosis misc Feasibility analysis misc Immunotherapy misc Lymphocytes misc Gene expression misc CD4 antigen misc Antigens misc Lymphocytes T misc Mutations misc Thymus misc Patients misc Studies misc CD8 antigen misc Tumors misc Immunity misc Immunological tolerance misc Vaccination misc PD-1 protein misc Cell death misc Immunogenicity misc Peptides misc Mutation misc T cell receptors |
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ddc 070 ddc 500 fid BIODIV misc Melanoma misc Tumor antigens misc Vaccines misc Feasibility studies misc Histocompatibility antigen HLA misc Tissues misc Apoptosis misc Feasibility analysis misc Immunotherapy misc Lymphocytes misc Gene expression misc CD4 antigen misc Antigens misc Lymphocytes T misc Mutations misc Thymus misc Patients misc Studies misc CD8 antigen misc Tumors misc Immunity misc Immunological tolerance misc Vaccination misc PD-1 protein misc Cell death misc Immunogenicity misc Peptides misc Mutation misc T cell receptors |
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ddc 070 ddc 500 fid BIODIV misc Melanoma misc Tumor antigens misc Vaccines misc Feasibility studies misc Histocompatibility antigen HLA misc Tissues misc Apoptosis misc Feasibility analysis misc Immunotherapy misc Lymphocytes misc Gene expression misc CD4 antigen misc Antigens misc Lymphocytes T misc Mutations misc Thymus misc Patients misc Studies misc CD8 antigen misc Tumors misc Immunity misc Immunological tolerance misc Vaccination misc PD-1 protein misc Cell death misc Immunogenicity misc Peptides misc Mutation misc T cell receptors |
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An immunogenic personal neoantigen vaccine for patients with melanoma |
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An immunogenic personal neoantigen vaccine for patients with melanoma |
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Ott, Patrick A |
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Nature |
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Nature |
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eng |
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Ott, Patrick A |
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10.1038/nature22991 |
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immunogenic personal neoantigen vaccine for patients with melanoma |
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An immunogenic personal neoantigen vaccine for patients with melanoma |
| abstract |
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. |
| abstractGer |
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. |
| abstract_unstemmed |
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies. |
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| container_issue |
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| title_short |
An immunogenic personal neoantigen vaccine for patients with melanoma |
| url |
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| remote_bool |
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| author2 |
Hu, Zhuting Keskin, Derin B Shukla, Sachet A Sun, Jing Bozym, David J Zhang, Wandi Luoma, Adrienne Giobbie-Hurder, Anita Peter, Lauren Chen, Christina Olive, Oriol Carter, Todd A Li, Shuqiang Lieb, David J Eisenhaure, Thomas Gjini, Evisa Stevens, Jonathan Lane, William J Javeri, Indu Nellaiappan, Kaliappanadar Salazar, Andres M Daley, Heather Seaman, Michael Buchbinder, Elizabeth I Yoon, Charles H Harden, Maegan Lennon, Niall Gabriel, Stacey Rodig, Scott J Barouch, Dan H Aster, Jon C Getz, Gad Wucherpfennig, Kai Neuberg, Donna Ritz, Jerome Lander, Eric S Fritsch, Edward F Hacohen, Nir Wu, Catherine J |
| author2Str |
Hu, Zhuting Keskin, Derin B Shukla, Sachet A Sun, Jing Bozym, David J Zhang, Wandi Luoma, Adrienne Giobbie-Hurder, Anita Peter, Lauren Chen, Christina Olive, Oriol Carter, Todd A Li, Shuqiang Lieb, David J Eisenhaure, Thomas Gjini, Evisa Stevens, Jonathan Lane, William J Javeri, Indu Nellaiappan, Kaliappanadar Salazar, Andres M Daley, Heather Seaman, Michael Buchbinder, Elizabeth I Yoon, Charles H Harden, Maegan Lennon, Niall Gabriel, Stacey Rodig, Scott J Barouch, Dan H Aster, Jon C Getz, Gad Wucherpfennig, Kai Neuberg, Donna Ritz, Jerome Lander, Eric S Fritsch, Edward F Hacohen, Nir Wu, Catherine J |
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| doi_str |
10.1038/nature22991 |
| up_date |
2024-07-03T23:33:05.556Z |
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|
| score |
7.40141 |