Effect of Pemetrexed on Innate Immune Killer Cells and Adaptive Immune T Cells in Subjects With Adenocarcinoma of the Pancreas
Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural kille...
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| creator | DAVIS, Marcherie CONLON, Kevin BOHAC, Gerald C BARCENAS, John LESLIE, William WATKINS, Latanja LAMZABI, Ihab YOUPING DENG YAN LI PLATE, Janet M. D |
| description | Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted. |
| doi_str_mv | 10.1097/CJI.0b013e31826c8a4f |
| format | Article |
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D</creator><creatorcontrib>DAVIS, Marcherie ; CONLON, Kevin ; BOHAC, Gerald C ; BARCENAS, John ; LESLIE, William ; WATKINS, Latanja ; LAMZABI, Ihab ; YOUPING DENG ; YAN LI ; PLATE, Janet M. D</creatorcontrib><description>Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted.</description><identifier>ISSN: 1524-9557</identifier><identifier>EISSN: 1537-4513</identifier><identifier>DOI: 10.1097/CJI.0b013e31826c8a4f</identifier><identifier>PMID: 22996369</identifier><identifier>CODEN: JOIMF8</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Adaptive Immunity - drug effects ; Adenocarcinoma ; Adenocarcinoma - immunology ; Adenocarcinoma - mortality ; Adenocarcinoma - pathology ; Adenocarcinoma - therapy ; Aged ; Antineoplastic agents ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; B7 Antigens - immunology ; Biological and medical sciences ; CD8 antigen ; CD8-Positive T-Lymphocytes - drug effects ; CD8-Positive T-Lymphocytes - immunology ; Cell survival ; Clinical trials ; Cytotoxicity, Immunologic - drug effects ; Deoxycytidine - administration & dosage ; Deoxycytidine - adverse effects ; Deoxycytidine - analogs & derivatives ; Female ; Follow-Up Studies ; Forkhead Transcription Factors - metabolism ; Foxp3 protein ; gamma -Interferon ; Gastroenterology. Liver. Pancreas. Abdomen ; gemcitabine ; Glutamates - administration & dosage ; Glutamates - adverse effects ; Guanine - administration & dosage ; Guanine - adverse effects ; Guanine - analogs & derivatives ; Humans ; Immunity ; Immunity, Innate - drug effects ; Immunologic Memory - drug effects ; Immunological memory ; Immunotherapy ; Interferon-gamma - metabolism ; Interleukin 2 ; Interleukin-2 - metabolism ; Killer Cells, Natural - drug effects ; Killer Cells, Natural - immunology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Lymphocyte Count ; Lymphocytes T ; Male ; Medical sciences ; Memory cells ; Middle Aged ; Natural killer cells ; Pancreatic cancer ; Pancreatic Neoplasms - immunology ; Pancreatic Neoplasms - mortality ; Pancreatic Neoplasms - pathology ; Pancreatic Neoplasms - therapy ; Pemetrexed ; Pharmacology. Drug treatments ; Survival Analysis ; T-Lymphocyte Subsets - drug effects ; T-Lymphocyte Subsets - immunology ; Tumors</subject><ispartof>Journal of immunotherapy (1997), 2012-10, Vol.35 (8), p.629-640</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c370t-e807ba41277cc5e90e40b16c943734bcd99cb634ba6c2191dffd07e9fb8d9bac3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26450789$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22996369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DAVIS, Marcherie</creatorcontrib><creatorcontrib>CONLON, Kevin</creatorcontrib><creatorcontrib>BOHAC, Gerald C</creatorcontrib><creatorcontrib>BARCENAS, John</creatorcontrib><creatorcontrib>LESLIE, William</creatorcontrib><creatorcontrib>WATKINS, Latanja</creatorcontrib><creatorcontrib>LAMZABI, Ihab</creatorcontrib><creatorcontrib>YOUPING DENG</creatorcontrib><creatorcontrib>YAN LI</creatorcontrib><creatorcontrib>PLATE, Janet M. D</creatorcontrib><title>Effect of Pemetrexed on Innate Immune Killer Cells and Adaptive Immune T Cells in Subjects With Adenocarcinoma of the Pancreas</title><title>Journal of immunotherapy (1997)</title><addtitle>J Immunother</addtitle><description>Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted.</description><subject>Adaptive Immunity - drug effects</subject><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - immunology</subject><subject>Adenocarcinoma - mortality</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma - therapy</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>B7 Antigens - immunology</subject><subject>Biological and medical sciences</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes - drug effects</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cell survival</subject><subject>Clinical trials</subject><subject>Cytotoxicity, Immunologic - drug effects</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - adverse effects</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Foxp3 protein</subject><subject>gamma -Interferon</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>gemcitabine</subject><subject>Glutamates - administration & dosage</subject><subject>Glutamates - adverse effects</subject><subject>Guanine - administration & dosage</subject><subject>Guanine - adverse effects</subject><subject>Guanine - analogs & derivatives</subject><subject>Humans</subject><subject>Immunity</subject><subject>Immunity, Innate - drug effects</subject><subject>Immunologic Memory - drug effects</subject><subject>Immunological memory</subject><subject>Immunotherapy</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin 2</subject><subject>Interleukin-2 - metabolism</subject><subject>Killer Cells, Natural - drug effects</subject><subject>Killer Cells, Natural - immunology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Lymphocyte Count</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Memory cells</subject><subject>Middle Aged</subject><subject>Natural killer cells</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - immunology</subject><subject>Pancreatic Neoplasms - mortality</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pancreatic Neoplasms - therapy</subject><subject>Pemetrexed</subject><subject>Pharmacology. Drug treatments</subject><subject>Survival Analysis</subject><subject>T-Lymphocyte Subsets - drug effects</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>Tumors</subject><issn>1524-9557</issn><issn>1537-4513</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c9LHDEUB_Agirtd_Q-K5CL0Mppfk0yOy2LrtoKCischybzgyExmTWakvfRvN4tbC1485UE-772QL0JfKTmjRKvz1c_1GbGEcuC0YtJVRvg9NKclV4UoKd_f1kwUuizVDH1J6YkQJplgh2jGmNaSSz1Hfy-8BzfiweMb6GGM8BsaPAS8DsGMgNd9PwXAv9qug4hX0HUJm9DgZWM2Y_vyDu52d23At5N9yiMTfmjHxwwhDM5E14ahN9s94yPgGxNcBJOO0IE3XYLj3blA998v7laXxdX1j_VqeVU4rshYQEWUNYIypZwrQRMQxFLptOCKC-sarZ2VuTLSMapp431DFGhvq0Zb4_gCfXubu4nD8wRprPs2ufxiE2CYUk2ZppKqkpPPKZGakVKJLRVv1MUhpQi-3sS2N_FPRvU2pDqHVH8MKbed7DZMtofmvelfKhmc7oBJznQ-5t9q038nRUlUpfkrYHCbuQ</recordid><startdate>20121001</startdate><enddate>20121001</enddate><creator>DAVIS, Marcherie</creator><creator>CONLON, Kevin</creator><creator>BOHAC, Gerald C</creator><creator>BARCENAS, John</creator><creator>LESLIE, William</creator><creator>WATKINS, Latanja</creator><creator>LAMZABI, Ihab</creator><creator>YOUPING DENG</creator><creator>YAN LI</creator><creator>PLATE, Janet M. D</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><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>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20121001</creationdate><title>Effect of Pemetrexed on Innate Immune Killer Cells and Adaptive Immune T Cells in Subjects With Adenocarcinoma of the Pancreas</title><author>DAVIS, Marcherie ; CONLON, Kevin ; BOHAC, Gerald C ; BARCENAS, John ; LESLIE, William ; WATKINS, Latanja ; LAMZABI, Ihab ; YOUPING DENG ; YAN LI ; PLATE, Janet M. D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c370t-e807ba41277cc5e90e40b16c943734bcd99cb634ba6c2191dffd07e9fb8d9bac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adaptive Immunity - drug effects</topic><topic>Adenocarcinoma</topic><topic>Adenocarcinoma - immunology</topic><topic>Adenocarcinoma - mortality</topic><topic>Adenocarcinoma - pathology</topic><topic>Adenocarcinoma - therapy</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>B7 Antigens - immunology</topic><topic>Biological and medical sciences</topic><topic>CD8 antigen</topic><topic>CD8-Positive T-Lymphocytes - drug effects</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>Cell survival</topic><topic>Clinical trials</topic><topic>Cytotoxicity, Immunologic - drug effects</topic><topic>Deoxycytidine - administration & dosage</topic><topic>Deoxycytidine - adverse effects</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Foxp3 protein</topic><topic>gamma -Interferon</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>gemcitabine</topic><topic>Glutamates - administration & dosage</topic><topic>Glutamates - adverse effects</topic><topic>Guanine - administration & dosage</topic><topic>Guanine - adverse effects</topic><topic>Guanine - analogs & derivatives</topic><topic>Humans</topic><topic>Immunity</topic><topic>Immunity, Innate - drug effects</topic><topic>Immunologic Memory - drug effects</topic><topic>Immunological memory</topic><topic>Immunotherapy</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukin 2</topic><topic>Interleukin-2 - metabolism</topic><topic>Killer Cells, Natural - drug effects</topic><topic>Killer Cells, Natural - immunology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Lymphocyte Count</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Memory cells</topic><topic>Middle Aged</topic><topic>Natural killer cells</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - immunology</topic><topic>Pancreatic Neoplasms - mortality</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pancreatic Neoplasms - therapy</topic><topic>Pemetrexed</topic><topic>Pharmacology. Drug treatments</topic><topic>Survival Analysis</topic><topic>T-Lymphocyte Subsets - drug effects</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DAVIS, Marcherie</creatorcontrib><creatorcontrib>CONLON, Kevin</creatorcontrib><creatorcontrib>BOHAC, Gerald C</creatorcontrib><creatorcontrib>BARCENAS, John</creatorcontrib><creatorcontrib>LESLIE, William</creatorcontrib><creatorcontrib>WATKINS, Latanja</creatorcontrib><creatorcontrib>LAMZABI, Ihab</creatorcontrib><creatorcontrib>YOUPING DENG</creatorcontrib><creatorcontrib>YAN LI</creatorcontrib><creatorcontrib>PLATE, Janet M. 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D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of Pemetrexed on Innate Immune Killer Cells and Adaptive Immune T Cells in Subjects With Adenocarcinoma of the Pancreas</atitle><jtitle>Journal of immunotherapy (1997)</jtitle><addtitle>J Immunother</addtitle><date>2012-10-01</date><risdate>2012</risdate><volume>35</volume><issue>8</issue><spage>629</spage><epage>640</epage><pages>629-640</pages><issn>1524-9557</issn><eissn>1537-4513</eissn><coden>JOIMF8</coden><abstract>Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>22996369</pmid><doi>10.1097/CJI.0b013e31826c8a4f</doi><tpages>12</tpages></addata></record> |
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| ispartof | Journal of immunotherapy (1997), 2012-10, Vol.35 (8), p.629-640 |
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| subjects | Adaptive Immunity - drug effects Adenocarcinoma Adenocarcinoma - immunology Adenocarcinoma - mortality Adenocarcinoma - pathology Adenocarcinoma - therapy Aged Antineoplastic agents Antineoplastic Combined Chemotherapy Protocols - therapeutic use B7 Antigens - immunology Biological and medical sciences CD8 antigen CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology Cell survival Clinical trials Cytotoxicity, Immunologic - drug effects Deoxycytidine - administration & dosage Deoxycytidine - adverse effects Deoxycytidine - analogs & derivatives Female Follow-Up Studies Forkhead Transcription Factors - metabolism Foxp3 protein gamma -Interferon Gastroenterology. Liver. Pancreas. Abdomen gemcitabine Glutamates - administration & dosage Glutamates - adverse effects Guanine - administration & dosage Guanine - adverse effects Guanine - analogs & derivatives Humans Immunity Immunity, Innate - drug effects Immunologic Memory - drug effects Immunological memory Immunotherapy Interferon-gamma - metabolism Interleukin 2 Interleukin-2 - metabolism Killer Cells, Natural - drug effects Killer Cells, Natural - immunology Liver. Biliary tract. Portal circulation. Exocrine pancreas Lymphocyte Count Lymphocytes T Male Medical sciences Memory cells Middle Aged Natural killer cells Pancreatic cancer Pancreatic Neoplasms - immunology Pancreatic Neoplasms - mortality Pancreatic Neoplasms - pathology Pancreatic Neoplasms - therapy Pemetrexed Pharmacology. Drug treatments Survival Analysis T-Lymphocyte Subsets - drug effects T-Lymphocyte Subsets - immunology Tumors |
| title | Effect of Pemetrexed on Innate Immune Killer Cells and Adaptive Immune T Cells in Subjects With Adenocarcinoma of the Pancreas |
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