Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation
Oncolytic virus therapy can increase the immunogenicity of tumors and remodel the immunosuppressive tumor microenvironment, leading to an increased antitumor response to immune-checkpoint inhibitors. Here, we investigated the therapeutic potential of G47Δ, a third-generation oncolytic herpes simplex...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-09-01
|
| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S237277052100070X |
| _version_ | 1819129556858044416 |
|---|---|
| author | Kotaro Sugawara Miwako Iwai Hirotaka Ito Minoru Tanaka Yasuyuki Seto Tomoki Todo |
| author_facet | Kotaro Sugawara Miwako Iwai Hirotaka Ito Minoru Tanaka Yasuyuki Seto Tomoki Todo |
| author_sort | Kotaro Sugawara |
| collection | DOAJ |
| description | Oncolytic virus therapy can increase the immunogenicity of tumors and remodel the immunosuppressive tumor microenvironment, leading to an increased antitumor response to immune-checkpoint inhibitors. Here, we investigated the therapeutic potential of G47Δ, a third-generation oncolytic herpes simplex virus type 1, in combination with immune-checkpoint inhibitors using various syngeneic murine subcutaneous tumor models. Intratumoral inoculations with G47Δ and systemic anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody administration caused an enhanced antitumor activity when combined and worked synergistically. Conversely, the efficacy of G47Δ in combination with anti-programmed cell death protein-1 (PD-1) antibody was equivalent to that of the anti-PD-1 antibody alone in all murine models examined. The combination of intratumoral G47Δ and systemic anti-CTLA-4 antibody was shown to recruit effector T cells into the tumor efficiently while decreasing regulatory T cells. Furthermore, a wide range of gene signatures related to inflammation, lymphoid lineage, and T cell activation was highly upregulated with the combination therapy, suggesting the conversion of immune-insusceptible tumors to immune susceptible. The therapeutic effect proved tumor specific and long lasting. Immune cell subset depletion studies demonstrated that CD4+ T cells were required for synergistic curative activity. The results depict the dynamics of immune modulation of the tumor microenvironment and provide a clinical rationale for using G47Δ with immune checkpoint inhibitors. |
| first_indexed | 2024-12-22T08:45:36Z |
| format | Article |
| id | doaj.art-9f62c1da69e747cfb25945cb77484257 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-22T08:45:36Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-9f62c1da69e747cfb25945cb774842572022-12-21T18:32:08ZengElsevierMolecular Therapy: Oncolytics2372-77052021-09-0122129142Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulationKotaro Sugawara0Miwako Iwai1Hirotaka Ito2Minoru Tanaka3Yasuyuki Seto4Tomoki Todo5Division of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDivision of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanDivision of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanDivision of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanDepartment of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, JapanDivision of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Corresponding author: Tomoki Todo, Division of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.Oncolytic virus therapy can increase the immunogenicity of tumors and remodel the immunosuppressive tumor microenvironment, leading to an increased antitumor response to immune-checkpoint inhibitors. Here, we investigated the therapeutic potential of G47Δ, a third-generation oncolytic herpes simplex virus type 1, in combination with immune-checkpoint inhibitors using various syngeneic murine subcutaneous tumor models. Intratumoral inoculations with G47Δ and systemic anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody administration caused an enhanced antitumor activity when combined and worked synergistically. Conversely, the efficacy of G47Δ in combination with anti-programmed cell death protein-1 (PD-1) antibody was equivalent to that of the anti-PD-1 antibody alone in all murine models examined. The combination of intratumoral G47Δ and systemic anti-CTLA-4 antibody was shown to recruit effector T cells into the tumor efficiently while decreasing regulatory T cells. Furthermore, a wide range of gene signatures related to inflammation, lymphoid lineage, and T cell activation was highly upregulated with the combination therapy, suggesting the conversion of immune-insusceptible tumors to immune susceptible. The therapeutic effect proved tumor specific and long lasting. Immune cell subset depletion studies demonstrated that CD4+ T cells were required for synergistic curative activity. The results depict the dynamics of immune modulation of the tumor microenvironment and provide a clinical rationale for using G47Δ with immune checkpoint inhibitors.http://www.sciencedirect.com/science/article/pii/S237277052100070Xoncolytic virus therapyG47ΔCTLA-4PD-1immune-checkpoint inhibitorsherpes simplex virus type 1 |
| spellingShingle | Kotaro Sugawara Miwako Iwai Hirotaka Ito Minoru Tanaka Yasuyuki Seto Tomoki Todo Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation Molecular Therapy: Oncolytics oncolytic virus therapy G47Δ CTLA-4 PD-1 immune-checkpoint inhibitors herpes simplex virus type 1 |
| title | Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation |
| title_full | Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation |
| title_fullStr | Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation |
| title_full_unstemmed | Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation |
| title_short | Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation |
| title_sort | oncolytic herpes virus g47δ works synergistically with ctla 4 inhibition via dynamic intratumoral immune modulation |
| topic | oncolytic virus therapy G47Δ CTLA-4 PD-1 immune-checkpoint inhibitors herpes simplex virus type 1 |
| url | http://www.sciencedirect.com/science/article/pii/S237277052100070X |
| work_keys_str_mv | AT kotarosugawara oncolyticherpesvirusg47dworkssynergisticallywithctla4inhibitionviadynamicintratumoralimmunemodulation AT miwakoiwai oncolyticherpesvirusg47dworkssynergisticallywithctla4inhibitionviadynamicintratumoralimmunemodulation AT hirotakaito oncolyticherpesvirusg47dworkssynergisticallywithctla4inhibitionviadynamicintratumoralimmunemodulation AT minorutanaka oncolyticherpesvirusg47dworkssynergisticallywithctla4inhibitionviadynamicintratumoralimmunemodulation AT yasuyukiseto oncolyticherpesvirusg47dworkssynergisticallywithctla4inhibitionviadynamicintratumoralimmunemodulation AT tomokitodo oncolyticherpesvirusg47dworkssynergisticallywithctla4inhibitionviadynamicintratumoralimmunemodulation |