Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy
Diffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children. It is characterised for having a non-inflammatory microenvironment and be immunologically inert. Therefore, strategies aiming to break the microenvironment status-quo in this disease could provide...
| Autores: | , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/115584 |
| Acceso en línea: | https://hdl.handle.net/10171/115584 |
| Access Level: | acceso abierto |
| Palabra clave: | Diffuse Intrinsic Pontine Gliomas (DIPG) Oncolytic virus |
| id |
ES_7f3cbc7d002db683ce265cbdd98948b5 |
|---|---|
| oai_identifier_str |
oai:dadun.unav.edu:10171/115584 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| spelling |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacyPuigdelloses-Vallcorba, M. (Montserrat)|||/items/658120d0-6a3c-4bf3-9446-33a9234f787eLaspidea, V. (Virginia)|||/items/16d4f649-0742-47dc-a391-881d6cfb978fHambardzumyan, D. (Dolores)|||/items/29d0a56c-6206-4f90-8dc6-0735a59a4bd0Chen, Z. (ZhiHong)|||/items/72a3fee4-609d-4b1b-9bbf-7b72bc12bbf5Gupta, S. (Sumit)|||/items/b67dfb2a-67f2-4b16-a7ed-ff0f9f2492dcGomez-Manzano, C. (Candelaria)|||/items/5e8d7495-6be8-46e1-8303-cfd722d30166Labiano-Almiñana, S. (Sara)|||/items/65de3442-2f0f-4c20-8e40-43525bb58657Becher, O.J. (Oren J.)|||/items/8218a203-30af-4259-a7fc-91aa4e2c1faaWoodruff, T.M. (Trent M.)|||/items/ddf8ddd0-e56b-4a25-9128-c37dd043920cPio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95Ajona, D. (Daniel)|||/items/33f1d5ec-5a97-4d7f-a428-499e5075fc78Gallego-Perez-Larraya, J. (Jaime)|||/items/8a92f20a-1e24-427d-8da0-ace4eba5620dAlonso-Roldán, M.M. (Marta María)|||/items/b912e21e-f895-4efe-bc4c-de1ca8f36c37Diffuse Intrinsic Pontine Gliomas (DIPG)Oncolytic virusDiffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children. It is characterised for having a non-inflammatory microenvironment and be immunologically inert. Therefore, strategies aiming to break the microenvironment status-quo in this disease could provide therapeutic benefit. The complement system promotes tumor progression due to the continuous production of anaphylatoxins leading to the infiltration of myeloid cells, which express high levels of complement receptors (C3aR and C5aR1). We have in silico data showing the high expression of C5aR1 in DIPGs. Thus, we wanted to assess first whether complement C5aR1 could constitute an actionable target, and second whether combining C5aR1 inhibitors with oncolytic virus could result in a superior antitumor immune response than either agent alone in DIPG. In this study, we used two different peptide inhibitors of C5aR1, PMX53 and PMX205 combined with the virus Delta-24-ACT (an oncolytic virus armed with 4-1BBL). We performed in vivo studies to evaluate the efficacy of this combination in immunocompetent DIPG models. Our data showed that the combination Delta-24-ACT/PMX53 significantly extended the median survival of the animals when compared with either agent alone, and led to long-term survivors that generated immune memory. The combination treatment modulated the tumor microenvironment promoting an increase in lymphocytes, mainly CD8+ cells presenting an active phenotype, and a reduction in C5aR1 expression in the myeloid compartment. We are currently evaluating in vivo whether PMX205, which has an improved ability to cross the blood brain barrier, leads to better therapeutic response. In summary, the combination of Delta-24-ACT with a C5aR1 inhibitor showed the capacity to shake the DIPG tumor microenvironment and unleashed an antitumor immune response. These data underscore the possibilities to combine oncolytic virus with targets of the tumor microenvironment to improve their therapeutic benefit in DIPGs.Oxford University PressDadun. Depósito Académico Digital Universidad de Navarra20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/115584reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/1155842026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy |
| title |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy |
| spellingShingle |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy Puigdelloses-Vallcorba, M. (Montserrat)|||/items/658120d0-6a3c-4bf3-9446-33a9234f787e Diffuse Intrinsic Pontine Gliomas (DIPG) Oncolytic virus |
| title_short |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy |
| title_full |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy |
| title_fullStr |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy |
| title_full_unstemmed |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy |
| title_sort |
Modulating the myeloid population in DIPG models with oncolytic virus and complement inhibitors shows therapeutic efficacy |
| dc.creator.none.fl_str_mv |
Puigdelloses-Vallcorba, M. (Montserrat)|||/items/658120d0-6a3c-4bf3-9446-33a9234f787e Laspidea, V. (Virginia)|||/items/16d4f649-0742-47dc-a391-881d6cfb978f Hambardzumyan, D. (Dolores)|||/items/29d0a56c-6206-4f90-8dc6-0735a59a4bd0 Chen, Z. (ZhiHong)|||/items/72a3fee4-609d-4b1b-9bbf-7b72bc12bbf5 Gupta, S. (Sumit)|||/items/b67dfb2a-67f2-4b16-a7ed-ff0f9f2492dc Gomez-Manzano, C. (Candelaria)|||/items/5e8d7495-6be8-46e1-8303-cfd722d30166 Labiano-Almiñana, S. (Sara)|||/items/65de3442-2f0f-4c20-8e40-43525bb58657 Becher, O.J. (Oren J.)|||/items/8218a203-30af-4259-a7fc-91aa4e2c1faa Woodruff, T.M. (Trent M.)|||/items/ddf8ddd0-e56b-4a25-9128-c37dd043920c Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95 Ajona, D. (Daniel)|||/items/33f1d5ec-5a97-4d7f-a428-499e5075fc78 Gallego-Perez-Larraya, J. (Jaime)|||/items/8a92f20a-1e24-427d-8da0-ace4eba5620d Alonso-Roldán, M.M. (Marta María)|||/items/b912e21e-f895-4efe-bc4c-de1ca8f36c37 |
| author |
Puigdelloses-Vallcorba, M. (Montserrat)|||/items/658120d0-6a3c-4bf3-9446-33a9234f787e |
| author_facet |
Puigdelloses-Vallcorba, M. (Montserrat)|||/items/658120d0-6a3c-4bf3-9446-33a9234f787e Laspidea, V. (Virginia)|||/items/16d4f649-0742-47dc-a391-881d6cfb978f Hambardzumyan, D. (Dolores)|||/items/29d0a56c-6206-4f90-8dc6-0735a59a4bd0 Chen, Z. (ZhiHong)|||/items/72a3fee4-609d-4b1b-9bbf-7b72bc12bbf5 Gupta, S. (Sumit)|||/items/b67dfb2a-67f2-4b16-a7ed-ff0f9f2492dc Gomez-Manzano, C. (Candelaria)|||/items/5e8d7495-6be8-46e1-8303-cfd722d30166 Labiano-Almiñana, S. (Sara)|||/items/65de3442-2f0f-4c20-8e40-43525bb58657 Becher, O.J. (Oren J.)|||/items/8218a203-30af-4259-a7fc-91aa4e2c1faa Woodruff, T.M. (Trent M.)|||/items/ddf8ddd0-e56b-4a25-9128-c37dd043920c Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95 Ajona, D. (Daniel)|||/items/33f1d5ec-5a97-4d7f-a428-499e5075fc78 Gallego-Perez-Larraya, J. (Jaime)|||/items/8a92f20a-1e24-427d-8da0-ace4eba5620d Alonso-Roldán, M.M. (Marta María)|||/items/b912e21e-f895-4efe-bc4c-de1ca8f36c37 |
| author_role |
author |
| author2 |
Laspidea, V. (Virginia)|||/items/16d4f649-0742-47dc-a391-881d6cfb978f Hambardzumyan, D. (Dolores)|||/items/29d0a56c-6206-4f90-8dc6-0735a59a4bd0 Chen, Z. (ZhiHong)|||/items/72a3fee4-609d-4b1b-9bbf-7b72bc12bbf5 Gupta, S. (Sumit)|||/items/b67dfb2a-67f2-4b16-a7ed-ff0f9f2492dc Gomez-Manzano, C. (Candelaria)|||/items/5e8d7495-6be8-46e1-8303-cfd722d30166 Labiano-Almiñana, S. (Sara)|||/items/65de3442-2f0f-4c20-8e40-43525bb58657 Becher, O.J. (Oren J.)|||/items/8218a203-30af-4259-a7fc-91aa4e2c1faa Woodruff, T.M. (Trent M.)|||/items/ddf8ddd0-e56b-4a25-9128-c37dd043920c Pio, R. (Rubén)|||/items/d5c409b3-dbed-4f0c-8bad-94c31e0e5a95 Ajona, D. (Daniel)|||/items/33f1d5ec-5a97-4d7f-a428-499e5075fc78 Gallego-Perez-Larraya, J. (Jaime)|||/items/8a92f20a-1e24-427d-8da0-ace4eba5620d Alonso-Roldán, M.M. (Marta María)|||/items/b912e21e-f895-4efe-bc4c-de1ca8f36c37 |
| author2_role |
author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Diffuse Intrinsic Pontine Gliomas (DIPG) Oncolytic virus |
| topic |
Diffuse Intrinsic Pontine Gliomas (DIPG) Oncolytic virus |
| description |
Diffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children. It is characterised for having a non-inflammatory microenvironment and be immunologically inert. Therefore, strategies aiming to break the microenvironment status-quo in this disease could provide therapeutic benefit. The complement system promotes tumor progression due to the continuous production of anaphylatoxins leading to the infiltration of myeloid cells, which express high levels of complement receptors (C3aR and C5aR1). We have in silico data showing the high expression of C5aR1 in DIPGs. Thus, we wanted to assess first whether complement C5aR1 could constitute an actionable target, and second whether combining C5aR1 inhibitors with oncolytic virus could result in a superior antitumor immune response than either agent alone in DIPG. In this study, we used two different peptide inhibitors of C5aR1, PMX53 and PMX205 combined with the virus Delta-24-ACT (an oncolytic virus armed with 4-1BBL). We performed in vivo studies to evaluate the efficacy of this combination in immunocompetent DIPG models. Our data showed that the combination Delta-24-ACT/PMX53 significantly extended the median survival of the animals when compared with either agent alone, and led to long-term survivors that generated immune memory. The combination treatment modulated the tumor microenvironment promoting an increase in lymphocytes, mainly CD8+ cells presenting an active phenotype, and a reduction in C5aR1 expression in the myeloid compartment. We are currently evaluating in vivo whether PMX205, which has an improved ability to cross the blood brain barrier, leads to better therapeutic response. In summary, the combination of Delta-24-ACT with a C5aR1 inhibitor showed the capacity to shake the DIPG tumor microenvironment and unleashed an antitumor immune response. These data underscore the possibilities to combine oncolytic virus with targets of the tumor microenvironment to improve their therapeutic benefit in DIPGs. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021-01-01 2021 2021-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/115584 |
| url |
https://hdl.handle.net/10171/115584 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Oxford University Press |
| publisher.none.fl_str_mv |
Oxford University Press |
| dc.source.none.fl_str_mv |
reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
| instname_str |
Universidad de Navarra |
| reponame_str |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
| collection |
Dadun. Depósito Académico Digital de la Universidad de Navarra |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869411809422737408 |
| score |
15.811543 |