An immunogenic personal neoantigen vaccine for patients with melanoma
The results of a phase I trial assessing a personal neoantigen multi-peptide vaccine in patients with melanoma, showing feasibility, safety, and immunogenicity. Personalized cancer vaccine trials Neoantigens have long been considered optimal targets for anti-tumour vaccines, and recent mutation codi...
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creator | Ott, Patrick A. 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. |
description | The results of a phase I trial assessing a personal neoantigen multi-peptide vaccine in patients with melanoma, showing feasibility, safety, and immunogenicity.
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.
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens
1
, 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 response
2
, 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 enhan |
doi_str_mv | 10.1038/nature22991 |
format | Article |
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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.
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens
1
, 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 response
2
, 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.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature22991</identifier><identifier>PMID: 28678778</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/21 ; 13/31 ; 13/51 ; 38/23 ; 38/91 ; 631/250/590/2030 ; 631/67/580 ; Amino Acid Sequence ; Antibodies, Monoclonal, Humanized - pharmacology ; Antibodies, Monoclonal, Humanized - therapeutic use ; Antigens ; Antigens, Neoplasm - chemistry ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - immunology ; Apoptosis ; Cancer treatment ; Cancer Vaccines - adverse effects ; Cancer Vaccines - chemistry ; Cancer Vaccines - immunology ; Care and treatment ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; Cell death ; Feasibility studies ; Gene expression ; High-Throughput Nucleotide Sequencing ; Histocompatibility antigen HLA ; Histocompatibility Antigens Class II - immunology ; Humanities and Social Sciences ; Humans ; Immune checkpoint ; Immunity ; Immunogenicity ; Immunological tolerance ; Immunotherapy ; letter ; Lymphocytes ; Lymphocytes T ; Machine Learning ; Melanoma ; Melanoma - genetics ; Melanoma - immunology ; Melanoma - therapy ; Methods ; multidisciplinary ; Mutation ; Neoantigens ; Neoplasm Recurrence, Local - immunology ; Neoplasm Recurrence, Local - prevention & control ; Patient Safety ; Patients ; PD-1 protein ; Peptides ; Precision Medicine - methods ; Programmed Cell Death 1 Receptor - antagonists & inhibitors ; Science ; T cell receptors ; Thymus ; Tumors ; Vaccination ; Vaccines</subject><ispartof>Nature (London), 2017-07, Vol.547 (7662), p.217-221</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 13, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c630t-7d75a8ee5c239b746e349371d65635fd7aa62da2d2d375bfb7fa202539e713c03</citedby><cites>FETCH-LOGICAL-c630t-7d75a8ee5c239b746e349371d65635fd7aa62da2d2d375bfb7fa202539e713c03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28678778$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ott, Patrick A.</creatorcontrib><creatorcontrib>Hu, Zhuting</creatorcontrib><creatorcontrib>Keskin, Derin B.</creatorcontrib><creatorcontrib>Shukla, Sachet A.</creatorcontrib><creatorcontrib>Sun, Jing</creatorcontrib><creatorcontrib>Bozym, David J.</creatorcontrib><creatorcontrib>Zhang, Wandi</creatorcontrib><creatorcontrib>Luoma, Adrienne</creatorcontrib><creatorcontrib>Giobbie-Hurder, Anita</creatorcontrib><creatorcontrib>Peter, Lauren</creatorcontrib><creatorcontrib>Chen, Christina</creatorcontrib><creatorcontrib>Olive, Oriol</creatorcontrib><creatorcontrib>Carter, Todd A.</creatorcontrib><creatorcontrib>Li, Shuqiang</creatorcontrib><creatorcontrib>Lieb, David J.</creatorcontrib><creatorcontrib>Eisenhaure, Thomas</creatorcontrib><creatorcontrib>Gjini, Evisa</creatorcontrib><creatorcontrib>Stevens, Jonathan</creatorcontrib><creatorcontrib>Lane, William J.</creatorcontrib><creatorcontrib>Javeri, Indu</creatorcontrib><creatorcontrib>Nellaiappan, Kaliappanadar</creatorcontrib><creatorcontrib>Salazar, Andres M.</creatorcontrib><creatorcontrib>Daley, Heather</creatorcontrib><creatorcontrib>Seaman, Michael</creatorcontrib><creatorcontrib>Buchbinder, Elizabeth I.</creatorcontrib><creatorcontrib>Yoon, Charles H.</creatorcontrib><creatorcontrib>Harden, Maegan</creatorcontrib><creatorcontrib>Lennon, Niall</creatorcontrib><creatorcontrib>Gabriel, Stacey</creatorcontrib><creatorcontrib>Rodig, Scott J.</creatorcontrib><creatorcontrib>Barouch, Dan H.</creatorcontrib><creatorcontrib>Aster, Jon C.</creatorcontrib><creatorcontrib>Getz, Gad</creatorcontrib><creatorcontrib>Wucherpfennig, Kai</creatorcontrib><creatorcontrib>Neuberg, Donna</creatorcontrib><creatorcontrib>Ritz, Jerome</creatorcontrib><creatorcontrib>Lander, Eric S.</creatorcontrib><creatorcontrib>Fritsch, Edward F.</creatorcontrib><creatorcontrib>Hacohen, Nir</creatorcontrib><creatorcontrib>Wu, Catherine J.</creatorcontrib><title>An immunogenic personal neoantigen vaccine for patients with melanoma</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>The results of a phase I trial assessing a personal neoantigen multi-peptide vaccine in patients with melanoma, showing feasibility, safety, and immunogenicity.
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.
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens
1
, 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 response
2
, 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.</description><subject>13/1</subject><subject>13/106</subject><subject>13/21</subject><subject>13/31</subject><subject>13/51</subject><subject>38/23</subject><subject>38/91</subject><subject>631/250/590/2030</subject><subject>631/67/580</subject><subject>Amino Acid Sequence</subject><subject>Antibodies, Monoclonal, Humanized - pharmacology</subject><subject>Antibodies, Monoclonal, Humanized - therapeutic use</subject><subject>Antigens</subject><subject>Antigens, Neoplasm - chemistry</subject><subject>Antigens, Neoplasm - genetics</subject><subject>Antigens, Neoplasm - immunology</subject><subject>Apoptosis</subject><subject>Cancer treatment</subject><subject>Cancer Vaccines - adverse effects</subject><subject>Cancer Vaccines - chemistry</subject><subject>Cancer Vaccines - immunology</subject><subject>Care and treatment</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cell death</subject><subject>Feasibility studies</subject><subject>Gene expression</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Histocompatibility antigen HLA</subject><subject>Histocompatibility Antigens Class II - immunology</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immune checkpoint</subject><subject>Immunity</subject><subject>Immunogenicity</subject><subject>Immunological tolerance</subject><subject>Immunotherapy</subject><subject>letter</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Machine Learning</subject><subject>Melanoma</subject><subject>Melanoma - genetics</subject><subject>Melanoma - immunology</subject><subject>Melanoma - therapy</subject><subject>Methods</subject><subject>multidisciplinary</subject><subject>Mutation</subject><subject>Neoantigens</subject><subject>Neoplasm Recurrence, Local - immunology</subject><subject>Neoplasm Recurrence, Local - prevention & control</subject><subject>Patient Safety</subject><subject>Patients</subject><subject>PD-1 protein</subject><subject>Peptides</subject><subject>Precision Medicine - methods</subject><subject>Programmed Cell Death 1 Receptor - antagonists & inhibitors</subject><subject>Science</subject><subject>T cell receptors</subject><subject>Thymus</subject><subject>Tumors</subject><subject>Vaccination</subject><subject>Vaccines</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp10t1rFDEQAPAgij2rT77LYp9Et2aT3ST7eBytFoqCVnwMc9nZM2U32SZZP_77Rlr1DlbmITD5ZZgMQ8jzip5WlKu3DtIckLG2rR6QVVVLUdZCyYdkRSlTJVVcHJEnMV5TSptK1o_JEVNCKinVipytXWHHcXZ-h86aYsIQvYOhcOjBJZuzxXcwxjoseh-KCZJFl2Lxw6ZvxYgDOD_CU_KohyHis_vzmHw5P7vavC8vP7672KwvSyM4TaXsZAMKsTGMt1tZC-R1y2XViUbwpu8kgGAdsI51XDbbfit7YJQ1vEVZcUP5MTm5qzsFfzNjTPrazyG3G3XVZskYpfU_tYMBtXW9TwHMaKPR67pVPIfkWZULKv8XAwzeYW9z-sC_XPBmsjd6H50uoBwdjtYsVn118CCbhD_TDuYY9cXnT4f29f_t-urr5sOiNsHHGLDXU7AjhF-6ovr34ui9xcn6xf1k5-2I3V_7Z1MyeHMHYr5yOwx7o1-odwvZEcku</recordid><startdate>20170713</startdate><enddate>20170713</enddate><creator>Ott, Patrick A.</creator><creator>Hu, Zhuting</creator><creator>Keskin, Derin B.</creator><creator>Shukla, Sachet A.</creator><creator>Sun, Jing</creator><creator>Bozym, David J.</creator><creator>Zhang, Wandi</creator><creator>Luoma, Adrienne</creator><creator>Giobbie-Hurder, Anita</creator><creator>Peter, Lauren</creator><creator>Chen, Christina</creator><creator>Olive, Oriol</creator><creator>Carter, Todd A.</creator><creator>Li, Shuqiang</creator><creator>Lieb, David J.</creator><creator>Eisenhaure, Thomas</creator><creator>Gjini, Evisa</creator><creator>Stevens, Jonathan</creator><creator>Lane, William J.</creator><creator>Javeri, Indu</creator><creator>Nellaiappan, Kaliappanadar</creator><creator>Salazar, Andres M.</creator><creator>Daley, Heather</creator><creator>Seaman, Michael</creator><creator>Buchbinder, Elizabeth I.</creator><creator>Yoon, Charles H.</creator><creator>Harden, Maegan</creator><creator>Lennon, Niall</creator><creator>Gabriel, Stacey</creator><creator>Rodig, Scott 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immunogenic personal neoantigen vaccine for patients with melanoma</title><author>Ott, Patrick A. ; 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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c630t-7d75a8ee5c239b746e349371d65635fd7aa62da2d2d375bfb7fa202539e713c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/21</topic><topic>13/31</topic><topic>13/51</topic><topic>38/23</topic><topic>38/91</topic><topic>631/250/590/2030</topic><topic>631/67/580</topic><topic>Amino Acid Sequence</topic><topic>Antibodies, Monoclonal, Humanized - pharmacology</topic><topic>Antibodies, Monoclonal, Humanized - therapeutic use</topic><topic>Antigens</topic><topic>Antigens, Neoplasm - chemistry</topic><topic>Antigens, Neoplasm - genetics</topic><topic>Antigens, Neoplasm - immunology</topic><topic>Apoptosis</topic><topic>Cancer treatment</topic><topic>Cancer Vaccines - adverse effects</topic><topic>Cancer Vaccines - chemistry</topic><topic>Cancer Vaccines - immunology</topic><topic>Care and treatment</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD8 antigen</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cell death</topic><topic>Feasibility studies</topic><topic>Gene expression</topic><topic>High-Throughput Nucleotide Sequencing</topic><topic>Histocompatibility antigen HLA</topic><topic>Histocompatibility Antigens Class II - immunology</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immune checkpoint</topic><topic>Immunity</topic><topic>Immunogenicity</topic><topic>Immunological tolerance</topic><topic>Immunotherapy</topic><topic>letter</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Machine Learning</topic><topic>Melanoma</topic><topic>Melanoma - genetics</topic><topic>Melanoma - immunology</topic><topic>Melanoma - therapy</topic><topic>Methods</topic><topic>multidisciplinary</topic><topic>Mutation</topic><topic>Neoantigens</topic><topic>Neoplasm Recurrence, Local - immunology</topic><topic>Neoplasm Recurrence, Local - prevention & control</topic><topic>Patient Safety</topic><topic>Patients</topic><topic>PD-1 protein</topic><topic>Peptides</topic><topic>Precision Medicine - methods</topic><topic>Programmed Cell Death 1 Receptor - antagonists & inhibitors</topic><topic>Science</topic><topic>T cell receptors</topic><topic>Thymus</topic><topic>Tumors</topic><topic>Vaccination</topic><topic>Vaccines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ott, Patrick A.</creatorcontrib><creatorcontrib>Hu, Zhuting</creatorcontrib><creatorcontrib>Keskin, Derin B.</creatorcontrib><creatorcontrib>Shukla, Sachet A.</creatorcontrib><creatorcontrib>Sun, Jing</creatorcontrib><creatorcontrib>Bozym, David J.</creatorcontrib><creatorcontrib>Zhang, Wandi</creatorcontrib><creatorcontrib>Luoma, Adrienne</creatorcontrib><creatorcontrib>Giobbie-Hurder, Anita</creatorcontrib><creatorcontrib>Peter, Lauren</creatorcontrib><creatorcontrib>Chen, Christina</creatorcontrib><creatorcontrib>Olive, Oriol</creatorcontrib><creatorcontrib>Carter, Todd A.</creatorcontrib><creatorcontrib>Li, Shuqiang</creatorcontrib><creatorcontrib>Lieb, David J.</creatorcontrib><creatorcontrib>Eisenhaure, Thomas</creatorcontrib><creatorcontrib>Gjini, Evisa</creatorcontrib><creatorcontrib>Stevens, Jonathan</creatorcontrib><creatorcontrib>Lane, William J.</creatorcontrib><creatorcontrib>Javeri, Indu</creatorcontrib><creatorcontrib>Nellaiappan, Kaliappanadar</creatorcontrib><creatorcontrib>Salazar, Andres M.</creatorcontrib><creatorcontrib>Daley, Heather</creatorcontrib><creatorcontrib>Seaman, Michael</creatorcontrib><creatorcontrib>Buchbinder, Elizabeth I.</creatorcontrib><creatorcontrib>Yoon, Charles H.</creatorcontrib><creatorcontrib>Harden, Maegan</creatorcontrib><creatorcontrib>Lennon, Niall</creatorcontrib><creatorcontrib>Gabriel, Stacey</creatorcontrib><creatorcontrib>Rodig, Scott J.</creatorcontrib><creatorcontrib>Barouch, Dan H.</creatorcontrib><creatorcontrib>Aster, Jon C.</creatorcontrib><creatorcontrib>Getz, Gad</creatorcontrib><creatorcontrib>Wucherpfennig, Kai</creatorcontrib><creatorcontrib>Neuberg, Donna</creatorcontrib><creatorcontrib>Ritz, Jerome</creatorcontrib><creatorcontrib>Lander, Eric S.</creatorcontrib><creatorcontrib>Fritsch, Edward F.</creatorcontrib><creatorcontrib>Hacohen, Nir</creatorcontrib><creatorcontrib>Wu, Catherine J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Middle School</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ott, Patrick A.</au><au>Hu, Zhuting</au><au>Keskin, Derin B.</au><au>Shukla, Sachet A.</au><au>Sun, Jing</au><au>Bozym, David J.</au><au>Zhang, Wandi</au><au>Luoma, Adrienne</au><au>Giobbie-Hurder, Anita</au><au>Peter, Lauren</au><au>Chen, Christina</au><au>Olive, Oriol</au><au>Carter, Todd A.</au><au>Li, Shuqiang</au><au>Lieb, David J.</au><au>Eisenhaure, Thomas</au><au>Gjini, Evisa</au><au>Stevens, Jonathan</au><au>Lane, William J.</au><au>Javeri, Indu</au><au>Nellaiappan, Kaliappanadar</au><au>Salazar, Andres M.</au><au>Daley, Heather</au><au>Seaman, Michael</au><au>Buchbinder, Elizabeth I.</au><au>Yoon, Charles H.</au><au>Harden, Maegan</au><au>Lennon, Niall</au><au>Gabriel, Stacey</au><au>Rodig, Scott J.</au><au>Barouch, Dan H.</au><au>Aster, Jon C.</au><au>Getz, Gad</au><au>Wucherpfennig, Kai</au><au>Neuberg, Donna</au><au>Ritz, Jerome</au><au>Lander, Eric S.</au><au>Fritsch, Edward F.</au><au>Hacohen, Nir</au><au>Wu, Catherine J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An immunogenic personal neoantigen vaccine for patients with melanoma</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2017-07-13</date><risdate>2017</risdate><volume>547</volume><issue>7662</issue><spage>217</spage><epage>221</epage><pages>217-221</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>The results of a phase I trial assessing a personal neoantigen multi-peptide vaccine in patients with melanoma, showing feasibility, safety, and immunogenicity.
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.
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens
1
, 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 response
2
, 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><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28678778</pmid><doi>10.1038/nature22991</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
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subjects | 13/1 13/106 13/21 13/31 13/51 38/23 38/91 631/250/590/2030 631/67/580 Amino Acid Sequence Antibodies, Monoclonal, Humanized - pharmacology Antibodies, Monoclonal, Humanized - therapeutic use Antigens Antigens, Neoplasm - chemistry Antigens, Neoplasm - genetics Antigens, Neoplasm - immunology Apoptosis Cancer treatment Cancer Vaccines - adverse effects Cancer Vaccines - chemistry Cancer Vaccines - immunology Care and treatment CD4 antigen CD4-Positive T-Lymphocytes - immunology CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell death Feasibility studies Gene expression High-Throughput Nucleotide Sequencing Histocompatibility antigen HLA Histocompatibility Antigens Class II - immunology Humanities and Social Sciences Humans Immune checkpoint Immunity Immunogenicity Immunological tolerance Immunotherapy letter Lymphocytes Lymphocytes T Machine Learning Melanoma Melanoma - genetics Melanoma - immunology Melanoma - therapy Methods multidisciplinary Mutation Neoantigens Neoplasm Recurrence, Local - immunology Neoplasm Recurrence, Local - prevention & control Patient Safety Patients PD-1 protein Peptides Precision Medicine - methods Programmed Cell Death 1 Receptor - antagonists & inhibitors Science T cell receptors Thymus Tumors Vaccination Vaccines |
title | An immunogenic personal neoantigen vaccine for patients with melanoma |
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