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
| Autor: | Karola Rittner, Eric Quéméneur, Murielle Gantzer, Julie Hortelano, Benoit Sansas, Marie-Christine Claudepierre, Kaïdre Bendjama, Christine Thioudellet, Virginie Nourtier, Christelle Remy-Ziller, Xavier Préville |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
PD-L1 medicine.drug_class medicine.medical_treatment Immunology Programmed Cell Death 1 Receptor Vaccinia virus Monoclonal antibody Cancer Vaccines B7-H1 Antigen 03 medical and health sciences Mice 0302 clinical medicine Antineoplastic Agents Immunological Carcinoma Non-Small-Cell Lung Cell Line Tumor PD-1 medicine Immunology and Allergy Animals Lung cancer Interleukin-7 receptor Modified Vaccinia virus Ankara Pharmacology Mice Inbred BALB C Membrane Glycoproteins business.industry Mucin-1 Immunotherapy immune checkpoint blockade medicine.disease Combined Modality Therapy Xenograft Model Antitumor Assays Granzyme B lung cancer 030104 developmental biology Nivolumab Treatment Outcome 030220 oncology & carcinogenesis Injections Intravenous Cancer research TG4010 business CD8 Research Paper |
| Zdroj: | Human Vaccines & Immunotherapeutics |
| ISSN: | 2164-554X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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