4ONovel dendritic cell based immunotherapy for advanced cancer

4ONovel dendritic cell based immunotherapy for advanced cancer

Abstract Background Immune-checkpoint inhibitors (ICI) such as Ipilumimab and Nivolumab have made long-term survival a real possibility for advanced cancer patients. Despite the success, only a proportion of patients receiving ICI show meaningful clinical benefit. Developing a more personalized trea...

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Veröffentlicht in:Annals of oncology 2019-10, Vol.30 (Supplement_5)
Hauptverfasser: Kaur, A P, Adhikaree, J, Franks, H, Patel, P, Jackson, A M
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container_issue Supplement_5
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container_title Annals of oncology
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creator Kaur, A P
Adhikaree, J
Franks, H
Patel, P
Jackson, A M
description Abstract Background Immune-checkpoint inhibitors (ICI) such as Ipilumimab and Nivolumab have made long-term survival a real possibility for advanced cancer patients. Despite the success, only a proportion of patients receiving ICI show meaningful clinical benefit. Developing a more personalized treatment strategy using patient’s own immune cells may be a promising approach for treating non-responding patients. Natural circulating dendritic cells (nDC) such as CD1c+ DC (cDC2) subset and plasmacytoid DC (pDC) are essential for efficient activation of immune responses after ICI therapy. Thus understanding the condition of these cells in patients and devising new strategies to improve their functions may help improve response to ICI in advanced cancer patients. Methods To investigate this we measured the number and phenotype of nDC in 29 advanced cancer patients versus 21 age and gender-matched healthy controls using flow cytometry. We further identified that inhibition of the p38 MAPK pathway using small molecule inhibitors in cDC2 cells increases their immune-stimulatory capacity, measured by functional assays. Results The number of pDC were significantly reduced in cancer patients as compared to healthy controls (1221 vs 2843 pDC/mL) (p-value
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Despite the success, only a proportion of patients receiving ICI show meaningful clinical benefit. Developing a more personalized treatment strategy using patient’s own immune cells may be a promising approach for treating non-responding patients. Natural circulating dendritic cells (nDC) such as CD1c+ DC (cDC2) subset and plasmacytoid DC (pDC) are essential for efficient activation of immune responses after ICI therapy. Thus understanding the condition of these cells in patients and devising new strategies to improve their functions may help improve response to ICI in advanced cancer patients. Methods To investigate this we measured the number and phenotype of nDC in 29 advanced cancer patients versus 21 age and gender-matched healthy controls using flow cytometry. We further identified that inhibition of the p38 MAPK pathway using small molecule inhibitors in cDC2 cells increases their immune-stimulatory capacity, measured by functional assays. Results The number of pDC were significantly reduced in cancer patients as compared to healthy controls (1221 vs 2843 pDC/mL) (p-value&lt;0.01). Although the number of cDC2 were slightly reduced in cancer patients (4476 vs 5053 of cDC2/mL), a good proportion of patients had sufficient number of DC eligible for a DC-based immunotherapy. Patient cDC2 were immune-suppressed with low secretion of immune-stimulatory cytokines (IL-12) and impaired homing to lymph-nodes. We identified that the p38 MAPK signalling pathway was controlling immune-suppression in cDC2 cells. Inhibiting this pathway restored the secretion of IL-12 in all patients (n = 5), increased the homing of DC to lymph-node chemokines, and prevented them from secreting the immune-suppressive cytokine, IL-10. Conclusions The number and phenotype of nDC are suppressed in advanced cancer patients. Inhibition of p38 MAPK can restore the function of patient cDC2 subset. Co-culture of these p38-inhibited cDC2 with pDC further show promising results important for developing advanced DC vaccines. Our study has paved the way for a phase I clinical trial of adoptive transfer of p38-MAPK inhibited cDC2 in 24 advanced cancer patients. Legal entity responsible for the study University of Nottingham. Funding University of Nottingham. Disclosure All authors have declared no conflicts of interest.</description><identifier>ISSN: 0923-7534</identifier><identifier>EISSN: 1569-8041</identifier><identifier>DOI: 10.1093/annonc/mdz238.003</identifier><language>eng</language><publisher>Oxford University Press</publisher><ispartof>Annals of oncology, 2019-10, Vol.30 (Supplement_5)</ispartof><rights>European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids></links><search><creatorcontrib>Kaur, A P</creatorcontrib><creatorcontrib>Adhikaree, J</creatorcontrib><creatorcontrib>Franks, H</creatorcontrib><creatorcontrib>Patel, P</creatorcontrib><creatorcontrib>Jackson, A M</creatorcontrib><title>4ONovel dendritic cell based immunotherapy for advanced cancer</title><title>Annals of oncology</title><description>Abstract Background Immune-checkpoint inhibitors (ICI) such as Ipilumimab and Nivolumab have made long-term survival a real possibility for advanced cancer patients. Despite the success, only a proportion of patients receiving ICI show meaningful clinical benefit. Developing a more personalized treatment strategy using patient’s own immune cells may be a promising approach for treating non-responding patients. Natural circulating dendritic cells (nDC) such as CD1c+ DC (cDC2) subset and plasmacytoid DC (pDC) are essential for efficient activation of immune responses after ICI therapy. Thus understanding the condition of these cells in patients and devising new strategies to improve their functions may help improve response to ICI in advanced cancer patients. Methods To investigate this we measured the number and phenotype of nDC in 29 advanced cancer patients versus 21 age and gender-matched healthy controls using flow cytometry. We further identified that inhibition of the p38 MAPK pathway using small molecule inhibitors in cDC2 cells increases their immune-stimulatory capacity, measured by functional assays. Results The number of pDC were significantly reduced in cancer patients as compared to healthy controls (1221 vs 2843 pDC/mL) (p-value&lt;0.01). Although the number of cDC2 were slightly reduced in cancer patients (4476 vs 5053 of cDC2/mL), a good proportion of patients had sufficient number of DC eligible for a DC-based immunotherapy. Patient cDC2 were immune-suppressed with low secretion of immune-stimulatory cytokines (IL-12) and impaired homing to lymph-nodes. We identified that the p38 MAPK signalling pathway was controlling immune-suppression in cDC2 cells. Inhibiting this pathway restored the secretion of IL-12 in all patients (n = 5), increased the homing of DC to lymph-node chemokines, and prevented them from secreting the immune-suppressive cytokine, IL-10. Conclusions The number and phenotype of nDC are suppressed in advanced cancer patients. Inhibition of p38 MAPK can restore the function of patient cDC2 subset. Co-culture of these p38-inhibited cDC2 with pDC further show promising results important for developing advanced DC vaccines. Our study has paved the way for a phase I clinical trial of adoptive transfer of p38-MAPK inhibited cDC2 in 24 advanced cancer patients. Legal entity responsible for the study University of Nottingham. Funding University of Nottingham. Disclosure All authors have declared no conflicts of interest.</description><issn>0923-7534</issn><issn>1569-8041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqVzrsOgjAYhuHGaCIeLsCtFyD6lwLaxcVonHRxb2pbI6YHUpAEr16I3oDTO3zf8CC0ILAiwOhaOOedXFv1Tuh2BUAHKCJZzuItpGSIImAJjTcZTcdoUlVPAMhZwiK0Sy9n32iDlXYqFHUhsdTG4JuotMKFtS_n64cOomzx3QcsVCOc7CbZJ8zQ6C5Mpee_TtHyeLjuT7F_lbwMhRWh5QR4b-RfI_8aeWekf94_FNNGpA</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Kaur, A P</creator><creator>Adhikaree, J</creator><creator>Franks, H</creator><creator>Patel, P</creator><creator>Jackson, A M</creator><general>Oxford University Press</general><scope/></search><sort><creationdate>20191001</creationdate><title>4ONovel dendritic cell based immunotherapy for advanced cancer</title><author>Kaur, A P ; Adhikaree, J ; Franks, H ; Patel, P ; Jackson, A M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-oup_primary_10_1093_annonc_mdz238_0033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaur, A P</creatorcontrib><creatorcontrib>Adhikaree, J</creatorcontrib><creatorcontrib>Franks, H</creatorcontrib><creatorcontrib>Patel, P</creatorcontrib><creatorcontrib>Jackson, A M</creatorcontrib><jtitle>Annals of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaur, A P</au><au>Adhikaree, J</au><au>Franks, H</au><au>Patel, P</au><au>Jackson, A M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>4ONovel dendritic cell based immunotherapy for advanced cancer</atitle><jtitle>Annals of oncology</jtitle><date>2019-10-01</date><risdate>2019</risdate><volume>30</volume><issue>Supplement_5</issue><issn>0923-7534</issn><eissn>1569-8041</eissn><abstract>Abstract Background Immune-checkpoint inhibitors (ICI) such as Ipilumimab and Nivolumab have made long-term survival a real possibility for advanced cancer patients. Despite the success, only a proportion of patients receiving ICI show meaningful clinical benefit. Developing a more personalized treatment strategy using patient’s own immune cells may be a promising approach for treating non-responding patients. Natural circulating dendritic cells (nDC) such as CD1c+ DC (cDC2) subset and plasmacytoid DC (pDC) are essential for efficient activation of immune responses after ICI therapy. Thus understanding the condition of these cells in patients and devising new strategies to improve their functions may help improve response to ICI in advanced cancer patients. Methods To investigate this we measured the number and phenotype of nDC in 29 advanced cancer patients versus 21 age and gender-matched healthy controls using flow cytometry. We further identified that inhibition of the p38 MAPK pathway using small molecule inhibitors in cDC2 cells increases their immune-stimulatory capacity, measured by functional assays. Results The number of pDC were significantly reduced in cancer patients as compared to healthy controls (1221 vs 2843 pDC/mL) (p-value&lt;0.01). Although the number of cDC2 were slightly reduced in cancer patients (4476 vs 5053 of cDC2/mL), a good proportion of patients had sufficient number of DC eligible for a DC-based immunotherapy. Patient cDC2 were immune-suppressed with low secretion of immune-stimulatory cytokines (IL-12) and impaired homing to lymph-nodes. We identified that the p38 MAPK signalling pathway was controlling immune-suppression in cDC2 cells. Inhibiting this pathway restored the secretion of IL-12 in all patients (n = 5), increased the homing of DC to lymph-node chemokines, and prevented them from secreting the immune-suppressive cytokine, IL-10. Conclusions The number and phenotype of nDC are suppressed in advanced cancer patients. Inhibition of p38 MAPK can restore the function of patient cDC2 subset. Co-culture of these p38-inhibited cDC2 with pDC further show promising results important for developing advanced DC vaccines. Our study has paved the way for a phase I clinical trial of adoptive transfer of p38-MAPK inhibited cDC2 in 24 advanced cancer patients. Legal entity responsible for the study University of Nottingham. Funding University of Nottingham. Disclosure All authors have declared no conflicts of interest.</abstract><pub>Oxford University Press</pub><doi>10.1093/annonc/mdz238.003</doi></addata></record>
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