Cargando…

Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors

BACKGROUND: With the rapid development of immune checkpoint inhibitors and neoantigen (NeoV)-based personalized tumor vaccines, tumor immunotherapy has shown promising therapeutic results. However, the limited efficacy of available tumor vaccines impedes the development of personalized tumor immunot...

Descripción completa

Detalles Bibliográficos
Autores principales: Du, Yang, Liu, Ye, Wang, Di, Bai, Hua, Wang, Zhijie, He, Xiran, Zhang, Pei, Tian, Jie, Wang, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883272/
https://www.ncbi.nlm.nih.gov/pubmed/35217574
http://dx.doi.org/10.1136/jitc-2021-003564
_version_ 1784659887875162112
author Du, Yang
Liu, Ye
Wang, Di
Bai, Hua
Wang, Zhijie
He, Xiran
Zhang, Pei
Tian, Jie
Wang, Jie
author_facet Du, Yang
Liu, Ye
Wang, Di
Bai, Hua
Wang, Zhijie
He, Xiran
Zhang, Pei
Tian, Jie
Wang, Jie
author_sort Du, Yang
collection PubMed
description BACKGROUND: With the rapid development of immune checkpoint inhibitors and neoantigen (NeoV)-based personalized tumor vaccines, tumor immunotherapy has shown promising therapeutic results. However, the limited efficacy of available tumor vaccines impedes the development of personalized tumor immunotherapy. In this study, we developed a novel tumor vaccine system and proposed combined therapeutic strategies for improving treatment effects. METHODS: We developed a novel tumor vaccine system comprising a newly synthesized peptidic microarchitecture (PMA) with high assembly efficacy. The PMA-trapped neoantigen vaccine was developed to codeliver tumor neoantigen and the Toll-like receptor 9 agonist CpG (NeoV), abbreviated as PMA-NeoV. A microfluidic chip was used to produce PMA particles in a uniform and precise manner. Vaccine effectiveness was investigated both in vitro and in vivo. The combined immunotherapeutic effect of PMA-NeoV with anti-programmed cell death ligand 1 antibody (aPD-L1) or with the phosphatidylinositol 3‑kinase γ (PI3Kγ) inhibitor IPI-549 was further tested in MC38 mouse tumor model. RESULTS: PMA-NeoV not only promoted codelivery of the tumor vaccine but also potentiated vaccine immunogenicity. Moreover, compared with free NeoV, PMA-NeoV significantly increased the number of tumor-infiltrating lymphocytes, promoted the neoantigen-specific systemic immune response, and suppressed murine colon MC38 tumor growth. Furthermore, PMA-NeoV increased the expression of programmed cell death receptor-1 on T lymphocytes, and in combination with aPD-L1 eradicated seven of eight MC38 tumors by rescuing exhausted T lymphocytes. Moreover, we combined the PMA-NeoV with the IPI-549, a molecular switch that controls immune suppression, and found that this combination significantly suppressed tumor growth and eradicated five of eight inoculated tumors, by switching suppressive macrophages to their active state and activating T cells to prime a robust tumor immune microenvironment. CONCLUSIONS: We developed a tumor vaccine delivery system and presented a promising personalized tumor vaccine-based therapeutic regimen in which a tumor vaccine delivery system is combined with an aPD-L1 or PI3Kγ inhibitor to improve tumor immunotherapy outcomes.
format Online
Article
Text
id pubmed-8883272
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-88832722022-03-17 Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors Du, Yang Liu, Ye Wang, Di Bai, Hua Wang, Zhijie He, Xiran Zhang, Pei Tian, Jie Wang, Jie J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: With the rapid development of immune checkpoint inhibitors and neoantigen (NeoV)-based personalized tumor vaccines, tumor immunotherapy has shown promising therapeutic results. However, the limited efficacy of available tumor vaccines impedes the development of personalized tumor immunotherapy. In this study, we developed a novel tumor vaccine system and proposed combined therapeutic strategies for improving treatment effects. METHODS: We developed a novel tumor vaccine system comprising a newly synthesized peptidic microarchitecture (PMA) with high assembly efficacy. The PMA-trapped neoantigen vaccine was developed to codeliver tumor neoantigen and the Toll-like receptor 9 agonist CpG (NeoV), abbreviated as PMA-NeoV. A microfluidic chip was used to produce PMA particles in a uniform and precise manner. Vaccine effectiveness was investigated both in vitro and in vivo. The combined immunotherapeutic effect of PMA-NeoV with anti-programmed cell death ligand 1 antibody (aPD-L1) or with the phosphatidylinositol 3‑kinase γ (PI3Kγ) inhibitor IPI-549 was further tested in MC38 mouse tumor model. RESULTS: PMA-NeoV not only promoted codelivery of the tumor vaccine but also potentiated vaccine immunogenicity. Moreover, compared with free NeoV, PMA-NeoV significantly increased the number of tumor-infiltrating lymphocytes, promoted the neoantigen-specific systemic immune response, and suppressed murine colon MC38 tumor growth. Furthermore, PMA-NeoV increased the expression of programmed cell death receptor-1 on T lymphocytes, and in combination with aPD-L1 eradicated seven of eight MC38 tumors by rescuing exhausted T lymphocytes. Moreover, we combined the PMA-NeoV with the IPI-549, a molecular switch that controls immune suppression, and found that this combination significantly suppressed tumor growth and eradicated five of eight inoculated tumors, by switching suppressive macrophages to their active state and activating T cells to prime a robust tumor immune microenvironment. CONCLUSIONS: We developed a tumor vaccine delivery system and presented a promising personalized tumor vaccine-based therapeutic regimen in which a tumor vaccine delivery system is combined with an aPD-L1 or PI3Kγ inhibitor to improve tumor immunotherapy outcomes. BMJ Publishing Group 2022-02-25 /pmc/articles/PMC8883272/ /pubmed/35217574 http://dx.doi.org/10.1136/jitc-2021-003564 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
spellingShingle Clinical/Translational Cancer Immunotherapy
Du, Yang
Liu, Ye
Wang, Di
Bai, Hua
Wang, Zhijie
He, Xiran
Zhang, Pei
Tian, Jie
Wang, Jie
Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors
title Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors
title_full Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors
title_fullStr Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors
title_full_unstemmed Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors
title_short Peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or PI3Kγ inhibitor can enhance immunogenicity and eradicate tumors
title_sort peptidic microarchitecture-trapped tumor vaccine combined with immune checkpoint inhibitor or pi3kγ inhibitor can enhance immunogenicity and eradicate tumors
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883272/
https://www.ncbi.nlm.nih.gov/pubmed/35217574
http://dx.doi.org/10.1136/jitc-2021-003564
work_keys_str_mv AT duyang peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT liuye peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT wangdi peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT baihua peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT wangzhijie peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT hexiran peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT zhangpei peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT tianjie peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors
AT wangjie peptidicmicroarchitecturetrappedtumorvaccinecombinedwithimmunecheckpointinhibitororpi3kginhibitorcanenhanceimmunogenicityanderadicatetumors