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Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory

Current immunotherapies have proven effective in strengthening anti-tumor immune responses but constant opposing signals from tumor cells and surrounding microenvironment eventually lead to immune escape. We hypothesize that in situ release of antigens and regulation of both the innate and adaptive...

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Autores principales: Alvero, Ayesha B., Fox, Alexandra, Madina, Bhaskara, Krady, Marie, Gogoi, Radhika, Chehade, Hussein, Nakaar, Valerian, Almassian, Bijan, Yarovinsky, Timur, Rutherford, Thomas, Mor, Gil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557730/
https://www.ncbi.nlm.nih.gov/pubmed/37808682
http://dx.doi.org/10.1101/2023.09.27.559828
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author Alvero, Ayesha B.
Fox, Alexandra
Madina, Bhaskara
Krady, Marie
Gogoi, Radhika
Chehade, Hussein
Nakaar, Valerian
Almassian, Bijan
Yarovinsky, Timur
Rutherford, Thomas
Mor, Gil
author_facet Alvero, Ayesha B.
Fox, Alexandra
Madina, Bhaskara
Krady, Marie
Gogoi, Radhika
Chehade, Hussein
Nakaar, Valerian
Almassian, Bijan
Yarovinsky, Timur
Rutherford, Thomas
Mor, Gil
author_sort Alvero, Ayesha B.
collection PubMed
description Current immunotherapies have proven effective in strengthening anti-tumor immune responses but constant opposing signals from tumor cells and surrounding microenvironment eventually lead to immune escape. We hypothesize that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system will provide a robust and long-term anti-tumor effect by creating immunological memory against the tumor. To achieve this, we developed CARG-2020, a virus-like-vesicle (VLV). It is a genetically modified and self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three transgenes: 1 ) the pleiotropic antitumor cytokine IL-12 in which the subunits (p35 and p40) are tethered together; 2) the extracellular domain (ECD) of the pro- tumor IL-17RA, which can serve as a dominant negative antagonist; and 3) shRNA for PD-L1. Using a mouse model of ovarian cancer, we demonstrate the oncolytic effect and immune modulatory capacities of CARG-2020. By enhancing IL-12 and blocking IL-17 and PD-L1, CARG-2020 successfully reactivates immune surveillance by promoting M1 instead of M2 macrophage differentiation, inhibiting MDSC expansion, and establishing a potent CD8+ T cell mediated anti-tumoral response. Furthermore, we demonstrate that this therapeutic approach provides tumor-specific and long-term protection preventing the establishment of new tumors. Our results provide rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance the anti-tumor response and to prevent recurrence.
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spelling pubmed-105577302023-10-07 Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory Alvero, Ayesha B. Fox, Alexandra Madina, Bhaskara Krady, Marie Gogoi, Radhika Chehade, Hussein Nakaar, Valerian Almassian, Bijan Yarovinsky, Timur Rutherford, Thomas Mor, Gil bioRxiv Article Current immunotherapies have proven effective in strengthening anti-tumor immune responses but constant opposing signals from tumor cells and surrounding microenvironment eventually lead to immune escape. We hypothesize that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system will provide a robust and long-term anti-tumor effect by creating immunological memory against the tumor. To achieve this, we developed CARG-2020, a virus-like-vesicle (VLV). It is a genetically modified and self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three transgenes: 1 ) the pleiotropic antitumor cytokine IL-12 in which the subunits (p35 and p40) are tethered together; 2) the extracellular domain (ECD) of the pro- tumor IL-17RA, which can serve as a dominant negative antagonist; and 3) shRNA for PD-L1. Using a mouse model of ovarian cancer, we demonstrate the oncolytic effect and immune modulatory capacities of CARG-2020. By enhancing IL-12 and blocking IL-17 and PD-L1, CARG-2020 successfully reactivates immune surveillance by promoting M1 instead of M2 macrophage differentiation, inhibiting MDSC expansion, and establishing a potent CD8+ T cell mediated anti-tumoral response. Furthermore, we demonstrate that this therapeutic approach provides tumor-specific and long-term protection preventing the establishment of new tumors. Our results provide rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance the anti-tumor response and to prevent recurrence. Cold Spring Harbor Laboratory 2023-09-29 /pmc/articles/PMC10557730/ /pubmed/37808682 http://dx.doi.org/10.1101/2023.09.27.559828 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Alvero, Ayesha B.
Fox, Alexandra
Madina, Bhaskara
Krady, Marie
Gogoi, Radhika
Chehade, Hussein
Nakaar, Valerian
Almassian, Bijan
Yarovinsky, Timur
Rutherford, Thomas
Mor, Gil
Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
title Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
title_full Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
title_fullStr Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
title_full_unstemmed Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
title_short Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
title_sort immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557730/
https://www.ncbi.nlm.nih.gov/pubmed/37808682
http://dx.doi.org/10.1101/2023.09.27.559828
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