Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model
TG4010, a Modified Vaccinia virus Ankara (MVA) expressing human mucin1 (MUC1) has demonstrated clinical benefit for patients suffering from advanced non-small cell lung cancer (NSCLC) in combination with chemotherapy. To support its development, preclinical experiments were performed with either TG4...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-01-01
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| Series: | Human Vaccines & Immunotherapeutics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/21645515.2017.1373921 |
| _version_ | 1797677570415656960 |
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| author | Christelle Remy-Ziller Christine Thioudellet Julie Hortelano Murielle Gantzer Virginie Nourtier Marie-Christine Claudepierre Benoit Sansas Xavier Préville Kaïdre Bendjama Eric Quemeneur Karola Rittner |
| author_facet | Christelle Remy-Ziller Christine Thioudellet Julie Hortelano Murielle Gantzer Virginie Nourtier Marie-Christine Claudepierre Benoit Sansas Xavier Préville Kaïdre Bendjama Eric Quemeneur Karola Rittner |
| author_sort | Christelle Remy-Ziller |
| collection | DOAJ |
| description | TG4010, a Modified Vaccinia virus Ankara (MVA) expressing human mucin1 (MUC1) has demonstrated clinical benefit for patients suffering from advanced non-small cell lung cancer (NSCLC) in combination with chemotherapy. To support its development, preclinical experiments were performed with either TG4010 or β-galactosidase-encoding MVA vector (MVA-βgal) in mice presenting tumors in the lung. Tumor growth was obtained after intravenous injection of CT26 murine colon cancer cells, engineered to express either MUC1 or βgal. Mice showed increased survival rates after repeated intravenous injections of TG4010 or MVA-βgal, compared to an empty MVA control vector. Treatment with MVA vectors led to the accumulation of CD3dimCD8dim T cells, with two subpopulations characterized as KLRG1+CD127− short-lived effector cells (SLECs), and KLRG1−CD127− early effector cells (EECs) comprising cells releasing IFNγ, Granzyme B and CD107a upon antigen-specific peptide stimulation. EECs were characterized by an up-regulation of PD-1. Tumor growth in the diseased lung correlated with the appearance of PD1+ Treg cells that partially disappeared after TG4010 treatment. At late stage of tumor development in the lung, PD-L1 was detected on CD45− tumor cells, on CD4+ cells, including Treg cells, on CD3+CD8+ and CD3dimCD8dim T lymphocytes, on NK cells, on MDSCs and on alveolar macrophages. We demonstrated that targeting the PD-1/PD-L1 pathway with blocking monoclonal antibodies several days after TG4010 treatment, at late stage of tumor development, enhanced the therapeutic protection induced by the vaccine, supporting the ongoing clinical evaluation of TG4010 immunotherapy in combination with Nivolumab. |
| first_indexed | 2024-03-11T22:47:12Z |
| format | Article |
| id | doaj.art-be5219aae58d45cb91af1c53f55493cc |
| institution | Directory Open Access Journal |
| issn | 2164-5515 2164-554X |
| language | English |
| last_indexed | 2024-03-11T22:47:12Z |
| publishDate | 2018-01-01 |
| publisher | Taylor & Francis Group |
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| series | Human Vaccines & Immunotherapeutics |
| spelling | doaj.art-be5219aae58d45cb91af1c53f55493cc2023-09-22T08:17:52ZengTaylor & Francis GroupHuman Vaccines & Immunotherapeutics2164-55152164-554X2018-01-0114114014510.1080/21645515.2017.13739211373921Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor modelChristelle Remy-Ziller0Christine Thioudellet1Julie Hortelano2Murielle Gantzer3Virginie Nourtier4Marie-Christine Claudepierre5Benoit Sansas6Xavier Préville7Kaïdre Bendjama8Eric Quemeneur9Karola Rittner10Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.Transgene S.A.TG4010, a Modified Vaccinia virus Ankara (MVA) expressing human mucin1 (MUC1) has demonstrated clinical benefit for patients suffering from advanced non-small cell lung cancer (NSCLC) in combination with chemotherapy. To support its development, preclinical experiments were performed with either TG4010 or β-galactosidase-encoding MVA vector (MVA-βgal) in mice presenting tumors in the lung. Tumor growth was obtained after intravenous injection of CT26 murine colon cancer cells, engineered to express either MUC1 or βgal. Mice showed increased survival rates after repeated intravenous injections of TG4010 or MVA-βgal, compared to an empty MVA control vector. Treatment with MVA vectors led to the accumulation of CD3dimCD8dim T cells, with two subpopulations characterized as KLRG1+CD127− short-lived effector cells (SLECs), and KLRG1−CD127− early effector cells (EECs) comprising cells releasing IFNγ, Granzyme B and CD107a upon antigen-specific peptide stimulation. EECs were characterized by an up-regulation of PD-1. Tumor growth in the diseased lung correlated with the appearance of PD1+ Treg cells that partially disappeared after TG4010 treatment. At late stage of tumor development in the lung, PD-L1 was detected on CD45− tumor cells, on CD4+ cells, including Treg cells, on CD3+CD8+ and CD3dimCD8dim T lymphocytes, on NK cells, on MDSCs and on alveolar macrophages. We demonstrated that targeting the PD-1/PD-L1 pathway with blocking monoclonal antibodies several days after TG4010 treatment, at late stage of tumor development, enhanced the therapeutic protection induced by the vaccine, supporting the ongoing clinical evaluation of TG4010 immunotherapy in combination with Nivolumab.http://dx.doi.org/10.1080/21645515.2017.1373921immune checkpoint blockadelung cancermodified vaccinia virus ankarapd-1pd-l1tg4010 |
| spellingShingle | Christelle Remy-Ziller Christine Thioudellet Julie Hortelano Murielle Gantzer Virginie Nourtier Marie-Christine Claudepierre Benoit Sansas Xavier Préville Kaïdre Bendjama Eric Quemeneur Karola Rittner Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model Human Vaccines & Immunotherapeutics immune checkpoint blockade lung cancer modified vaccinia virus ankara pd-1 pd-l1 tg4010 |
| title | Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model |
| title_full | Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model |
| title_fullStr | Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model |
| title_full_unstemmed | Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model |
| title_short | Sequential administration of MVA-based vaccines and PD-1/PD-L1-blocking antibodies confers measurable benefits on tumor growth and survival: Preclinical studies with MVA-βGal and MVA-MUC1 (TG4010) in a murine tumor model |
| title_sort | sequential administration of mva based vaccines and pd 1 pd l1 blocking antibodies confers measurable benefits on tumor growth and survival preclinical studies with mva βgal and mva muc1 tg4010 in a murine tumor model |
| topic | immune checkpoint blockade lung cancer modified vaccinia virus ankara pd-1 pd-l1 tg4010 |
| url | http://dx.doi.org/10.1080/21645515.2017.1373921 |
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