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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Veröffentlicht in:Nature (London) 2017-07, Vol.547 (7662), p.217-221
Hauptverfasser: 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.
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container_end_page 221
container_issue 7662
container_start_page 217
container_title Nature (London)
container_volume 547
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
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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 &amp; control ; Patient Safety ; Patients ; PD-1 protein ; Peptides ; Precision Medicine - methods ; Programmed Cell Death 1 Receptor - antagonists &amp; 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 &amp; 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 &amp; 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 J.</creator><creator>Barouch, Dan H.</creator><creator>Aster, Jon C.</creator><creator>Getz, Gad</creator><creator>Wucherpfennig, Kai</creator><creator>Neuberg, Donna</creator><creator>Ritz, Jerome</creator><creator>Lander, Eric S.</creator><creator>Fritsch, Edward F.</creator><creator>Hacohen, Nir</creator><creator>Wu, Catherine J.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ATWCN</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope></search><sort><creationdate>20170713</creationdate><title>An immunogenic personal neoantigen vaccine for patients with melanoma</title><author>Ott, Patrick A. ; 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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.</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>
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identifier ISSN: 0028-0836
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issn 0028-0836
1476-4687
language eng
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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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