Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer
A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival...
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| Veröffentlicht in: | Cancer Immunology, Immunotherapy Immunotherapy, 2015-08, Vol.64 (8), p.977-987 |
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| container_title | Cancer Immunology, Immunotherapy |
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| creator | Balint, Joseph P. Gabitzsch, Elizabeth S. Rice, Adrian Latchman, Yvette Xu, Younong Messerschmidt, Gerald L. Chaudhry, Arvind Morse, Michael A. Jones, Frank R. |
| description | A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations. |
| doi_str_mv | 10.1007/s00262-015-1706-4 |
| format | Article |
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We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.</description><identifier>ISSN: 0340-7004</identifier><identifier>EISSN: 1432-0851</identifier><identifier>DOI: 10.1007/s00262-015-1706-4</identifier><identifier>PMID: 25956394</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adenoviridae ; Adenovirus E1 Proteins - genetics ; Adenovirus E2 Proteins - genetics ; Adenoviruses ; Adult ; Aged ; Antigens ; Cancer Research ; Cancer Vaccines - immunology ; Cancer Vaccines - therapeutic use ; Cells, Cultured ; Clinical trials ; Colorectal cancer ; Colorectal Neoplasms - mortality ; Colorectal Neoplasms - pathology ; Colorectal Neoplasms - therapy ; Cytotoxicity, Immunologic ; Female ; Follow-Up Studies ; Humans ; Immunization ; Immunology ; Immunotherapy ; Interferon-gamma - metabolism ; Lymphocytes ; Male ; Medicine ; Medicine & Public Health ; Metastasis ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Staging ; Oligopeptides - genetics ; Oligopeptides - immunology ; Oncology ; Original Article ; Sequence Deletion - genetics ; Survival Analysis ; T-Lymphocyte Subsets - immunology ; T-Lymphocytes, Regulatory - immunology ; Vaccines</subject><ispartof>Cancer Immunology, Immunotherapy, 2015-08, Vol.64 (8), p.977-987</ispartof><rights>Springer-Verlag Berlin Heidelberg 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c573t-813eb80e47f692cd595d65d9541ae2428962aadaabc3f1d8b5a07c593eaf831f3</citedby><cites>FETCH-LOGICAL-c573t-813eb80e47f692cd595d65d9541ae2428962aadaabc3f1d8b5a07c593eaf831f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506904/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506904/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25956394$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Balint, Joseph P.</creatorcontrib><creatorcontrib>Gabitzsch, Elizabeth S.</creatorcontrib><creatorcontrib>Rice, Adrian</creatorcontrib><creatorcontrib>Latchman, Yvette</creatorcontrib><creatorcontrib>Xu, Younong</creatorcontrib><creatorcontrib>Messerschmidt, Gerald L.</creatorcontrib><creatorcontrib>Chaudhry, Arvind</creatorcontrib><creatorcontrib>Morse, Michael A.</creatorcontrib><creatorcontrib>Jones, Frank R.</creatorcontrib><title>Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer</title><title>Cancer Immunology, Immunotherapy</title><addtitle>Cancer Immunol Immunother</addtitle><addtitle>Cancer Immunol Immunother</addtitle><description>A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.</description><subject>Adenoviridae</subject><subject>Adenovirus E1 Proteins - genetics</subject><subject>Adenovirus E2 Proteins - genetics</subject><subject>Adenoviruses</subject><subject>Adult</subject><subject>Aged</subject><subject>Antigens</subject><subject>Cancer Research</subject><subject>Cancer Vaccines - immunology</subject><subject>Cancer Vaccines - therapeutic use</subject><subject>Cells, Cultured</subject><subject>Clinical trials</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Colorectal Neoplasms - therapy</subject><subject>Cytotoxicity, Immunologic</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Humans</subject><subject>Immunization</subject><subject>Immunology</subject><subject>Immunotherapy</subject><subject>Interferon-gamma - metabolism</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Staging</subject><subject>Oligopeptides - genetics</subject><subject>Oligopeptides - immunology</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Sequence Deletion - genetics</subject><subject>Survival Analysis</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Vaccines</subject><issn>0340-7004</issn><issn>1432-0851</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1ks9uEzEQxlcIREPhAbggS1yKlKW2d-1dXypFIfyRKnGBE0LWxJ5NXG3sYO8ulKfkkXCaUhUkTrZnPv9mxv6K4jmjrxmlzXmilEteUiZK1lBZ1g-KGaurHGkFe1jMaFXTsqG0PimepHSVN5wq9bg44UIJWal6Vvxa_RjQW7QEJ-hHGFzwJHQEyH4LCQk752SIDnqS4zYk5zdzkqDD4XpO3G43-rBB74w7nMFbEiaM0PckjXFyGUmgGzAepe7nDT-R727YZjUBO4E3aMvMyNduii-sIF9WrJyTFV-XX8vlanEm37wiExjjPBLnSQ8DlmmADRIT-hDRDLmQOaDi0-JRB33CZ7frafH57erT8n15-fHdh-XisjSiqYayZRWuW4p100nFjc0PYqWwStQMkNe8VZIDWIC1qTpm27UA2hihKoSurVhXnRYXR-5-XO_QGvRDnlvvo9tBvNYBnP47491Wb8Kka0GlonUGnN0CYvg2Yhr0ziWDfQ8ew5h0_lHFpOSqytKX_0ivwhh9Hk8zqaRSgiuaVeyoMjGkFLG7a4ZRffCLPvpFZ78c6FIfmnhxf4q7G38MkgX8KEg55TcY75X-L_U3C4nNfw</recordid><startdate>20150801</startdate><enddate>20150801</enddate><creator>Balint, Joseph P.</creator><creator>Gabitzsch, Elizabeth S.</creator><creator>Rice, Adrian</creator><creator>Latchman, Yvette</creator><creator>Xu, Younong</creator><creator>Messerschmidt, Gerald L.</creator><creator>Chaudhry, Arvind</creator><creator>Morse, Michael A.</creator><creator>Jones, Frank R.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20150801</creationdate><title>Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer</title><author>Balint, Joseph P. ; Gabitzsch, Elizabeth S. ; Rice, Adrian ; Latchman, Yvette ; Xu, Younong ; Messerschmidt, Gerald L. ; Chaudhry, Arvind ; Morse, Michael A. ; Jones, Frank R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c573t-813eb80e47f692cd595d65d9541ae2428962aadaabc3f1d8b5a07c593eaf831f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenoviridae</topic><topic>Adenovirus E1 Proteins - genetics</topic><topic>Adenovirus E2 Proteins - genetics</topic><topic>Adenoviruses</topic><topic>Adult</topic><topic>Aged</topic><topic>Antigens</topic><topic>Cancer Research</topic><topic>Cancer Vaccines - immunology</topic><topic>Cancer Vaccines - therapeutic use</topic><topic>Cells, Cultured</topic><topic>Clinical trials</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Colorectal Neoplasms - therapy</topic><topic>Cytotoxicity, Immunologic</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Immunization</topic><topic>Immunology</topic><topic>Immunotherapy</topic><topic>Interferon-gamma - metabolism</topic><topic>Lymphocytes</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Staging</topic><topic>Oligopeptides - genetics</topic><topic>Oligopeptides - immunology</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Sequence Deletion - genetics</topic><topic>Survival Analysis</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Vaccines</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Balint, Joseph P.</creatorcontrib><creatorcontrib>Gabitzsch, Elizabeth S.</creatorcontrib><creatorcontrib>Rice, Adrian</creatorcontrib><creatorcontrib>Latchman, Yvette</creatorcontrib><creatorcontrib>Xu, Younong</creatorcontrib><creatorcontrib>Messerschmidt, Gerald L.</creatorcontrib><creatorcontrib>Chaudhry, Arvind</creatorcontrib><creatorcontrib>Morse, Michael A.</creatorcontrib><creatorcontrib>Jones, Frank R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer Immunology, Immunotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Balint, Joseph P.</au><au>Gabitzsch, Elizabeth S.</au><au>Rice, Adrian</au><au>Latchman, Yvette</au><au>Xu, Younong</au><au>Messerschmidt, Gerald L.</au><au>Chaudhry, Arvind</au><au>Morse, Michael A.</au><au>Jones, Frank R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer</atitle><jtitle>Cancer Immunology, Immunotherapy</jtitle><stitle>Cancer Immunol Immunother</stitle><addtitle>Cancer Immunol Immunother</addtitle><date>2015-08-01</date><risdate>2015</risdate><volume>64</volume><issue>8</issue><spage>977</spage><epage>987</epage><pages>977-987</pages><issn>0340-7004</issn><eissn>1432-0851</eissn><abstract>A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>25956394</pmid><doi>10.1007/s00262-015-1706-4</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer Immunology, Immunotherapy, 2015-08, Vol.64 (8), p.977-987 |
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| language | eng |
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| source | MEDLINE; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | Adenoviridae Adenovirus E1 Proteins - genetics Adenovirus E2 Proteins - genetics Adenoviruses Adult Aged Antigens Cancer Research Cancer Vaccines - immunology Cancer Vaccines - therapeutic use Cells, Cultured Clinical trials Colorectal cancer Colorectal Neoplasms - mortality Colorectal Neoplasms - pathology Colorectal Neoplasms - therapy Cytotoxicity, Immunologic Female Follow-Up Studies Humans Immunization Immunology Immunotherapy Interferon-gamma - metabolism Lymphocytes Male Medicine Medicine & Public Health Metastasis Middle Aged Neoplasm Metastasis Neoplasm Staging Oligopeptides - genetics Oligopeptides - immunology Oncology Original Article Sequence Deletion - genetics Survival Analysis T-Lymphocyte Subsets - immunology T-Lymphocytes, Regulatory - immunology Vaccines |
| title | Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer |
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