Cargando…

Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model

BACKGROUND: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant r...

Descripción completa

Detalles Bibliográficos
Autores principales: Shankara Narayanan, Jayanth S, Hayashi, Tomoko, Erdem, Suna, McArdle, Sara, Tiriac, Herve, Ray, Partha, Pu, Minya, Mikulski, Zbigniew, Miller, Aaron, Messer, Karen, Carson, Dennis, Schoenberger, Stephen, White, Rebekah R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843215/
https://www.ncbi.nlm.nih.gov/pubmed/36634919
http://dx.doi.org/10.1136/jitc-2022-006133
_version_ 1784870339143008256
author Shankara Narayanan, Jayanth S
Hayashi, Tomoko
Erdem, Suna
McArdle, Sara
Tiriac, Herve
Ray, Partha
Pu, Minya
Mikulski, Zbigniew
Miller, Aaron
Messer, Karen
Carson, Dennis
Schoenberger, Stephen
White, Rebekah R
author_facet Shankara Narayanan, Jayanth S
Hayashi, Tomoko
Erdem, Suna
McArdle, Sara
Tiriac, Herve
Ray, Partha
Pu, Minya
Mikulski, Zbigniew
Miller, Aaron
Messer, Karen
Carson, Dennis
Schoenberger, Stephen
White, Rebekah R
author_sort Shankara Narayanan, Jayanth S
collection PubMed
description BACKGROUND: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here, we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab). METHODS: KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days postprocedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses. RESULTS: The combination of IRE+CD40 Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p<0.01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than twofold higher infiltration of CD8+T cells in the IRE+CD40 Ab group than in any other group (p<0.01). Multiplex immunofluorescence imaging revealed a 4–6 fold increase in the density of CD80+CD11c+ activated dendritic cells (p<0.05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p<0.05) and Ly6G+myeloid derived cells (p<0.01) were reduced and restricted to the tumor periphery in the IRE+CD40 Ab group. T-cells from the IRE+CD40 Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups. CONCLUSIONS: IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic antitumor T-cell response that inhibited metastatic disease progression.
format Online
Article
Text
id pubmed-9843215
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-98432152023-01-18 Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model Shankara Narayanan, Jayanth S Hayashi, Tomoko Erdem, Suna McArdle, Sara Tiriac, Herve Ray, Partha Pu, Minya Mikulski, Zbigniew Miller, Aaron Messer, Karen Carson, Dennis Schoenberger, Stephen White, Rebekah R J Immunother Cancer Oncolytic and Local Immunotherapy BACKGROUND: Pancreatic cancer (PC) has a poor prognosis, and most patients present with either locally advanced or distant metastatic disease. Irreversible electroporation (IRE) is a non-thermal method of ablation used clinically in locally advanced PC, but most patients eventually develop distant recurrence. We have previously shown that IRE alone is capable of generating protective, neoantigen-specific immunity. Here, we aim to generate meaningful therapeutic immune effects by combining IRE with local (intratumoral) delivery of a CD40 agonistic antibody (CD40Ab). METHODS: KPC46 organoids were generated from a tumor-bearing male KrasLSL-G12D-p53LSL-R172H-Pdx-1-Cre (KPC) mouse. Orthotopic tumors were established in the pancreatic tail of B6/129 F1J mice via laparotomy. Mice were randomized to treatment with either sham laparotomy, IRE alone, CD40Ab alone, or IRE followed immediately by CD40Ab injection. Metastatic disease and immune infiltration in the liver were analyzed 14 days postprocedure using flow cytometry and multiplex immunofluorescence imaging with spatial analysis. Candidate neoantigens were identified by mutanome profiling of tumor tissue for ex vivo functional analyses. RESULTS: The combination of IRE+CD40 Ab improved median survival to greater than 35 days, significantly longer than IRE (21 days) or CD40Ab (24 days) alone (p<0.01). CD40Ab decreased metastatic disease burden, with less disease in the combination group than in the sham group or IRE alone. Immunohistochemistry of liver metastases revealed a more than twofold higher infiltration of CD8+T cells in the IRE+CD40 Ab group than in any other group (p<0.01). Multiplex immunofluorescence imaging revealed a 4–6 fold increase in the density of CD80+CD11c+ activated dendritic cells (p<0.05), which were spatially distributed throughout the tumor unlike the sham group, where they were restricted to the periphery. In contrast, CD4+FoxP3+ T-regulatory cells (p<0.05) and Ly6G+myeloid derived cells (p<0.01) were reduced and restricted to the tumor periphery in the IRE+CD40 Ab group. T-cells from the IRE+CD40 Ab group recognized significantly more peptides representing candidate neoantigens than did T-cells from the IRE or untreated control groups. CONCLUSIONS: IRE can induce local tumor regression and neoantigen-specific immune responses. Addition of CD40Ab to IRE improved dendritic cell activation and neoantigen recognition, while generating a strong systemic antitumor T-cell response that inhibited metastatic disease progression. BMJ Publishing Group 2023-01-11 /pmc/articles/PMC9843215/ /pubmed/36634919 http://dx.doi.org/10.1136/jitc-2022-006133 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Oncolytic and Local Immunotherapy
Shankara Narayanan, Jayanth S
Hayashi, Tomoko
Erdem, Suna
McArdle, Sara
Tiriac, Herve
Ray, Partha
Pu, Minya
Mikulski, Zbigniew
Miller, Aaron
Messer, Karen
Carson, Dennis
Schoenberger, Stephen
White, Rebekah R
Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
title Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
title_full Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
title_fullStr Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
title_full_unstemmed Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
title_short Treatment of pancreatic cancer with irreversible electroporation and intratumoral CD40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
title_sort treatment of pancreatic cancer with irreversible electroporation and intratumoral cd40 antibody stimulates systemic immune responses that inhibit liver metastasis in an orthotopic model
topic Oncolytic and Local Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843215/
https://www.ncbi.nlm.nih.gov/pubmed/36634919
http://dx.doi.org/10.1136/jitc-2022-006133
work_keys_str_mv AT shankaranarayananjayanths treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT hayashitomoko treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT erdemsuna treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT mcardlesara treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT tiriacherve treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT raypartha treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT puminya treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT mikulskizbigniew treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT milleraaron treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT messerkaren treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT carsondennis treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT schoenbergerstephen treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel
AT whiterebekahr treatmentofpancreaticcancerwithirreversibleelectroporationandintratumoralcd40antibodystimulatessystemicimmuneresponsesthatinhibitlivermetastasisinanorthotopicmodel