Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models
Abstract Pancreatic ductal adenocarcinoma (PDAC) is a cancer with dismal prognosis due to resistance to most current therapies. Although immunotherapy has improved the treatment of many solid cancers, pancreatic cancer remains resistant to immunotherapy due to immunosuppressive tumor microenvironmen...
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Springer
2025-06-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04072-6 |
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| author | Santeri A. Pakola Nea Ojala Tatiana V. Kudling James H. A. Clubb Elise Jirovec Mirte van der Heijden Victor Arias Lyna Haybout Saru Basnet Susanna Grönberg-Vähä-Koskela Dafne C. A. Quixabeira Joao M. Santos Victor Cervera-Carrascon Otto Hemminki Anna Kanerva Harri Mustonen Pauli Puolakkainen Hanna Seppänen Akseli Hemminki |
| author_facet | Santeri A. Pakola Nea Ojala Tatiana V. Kudling James H. A. Clubb Elise Jirovec Mirte van der Heijden Victor Arias Lyna Haybout Saru Basnet Susanna Grönberg-Vähä-Koskela Dafne C. A. Quixabeira Joao M. Santos Victor Cervera-Carrascon Otto Hemminki Anna Kanerva Harri Mustonen Pauli Puolakkainen Hanna Seppänen Akseli Hemminki |
| author_sort | Santeri A. Pakola |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC) is a cancer with dismal prognosis due to resistance to most current therapies. Although immunotherapy has improved the treatment of many solid cancers, pancreatic cancer remains resistant to immunotherapy due to immunosuppressive tumor microenvironment, limited lymphocyte infiltration and lack of neoantigens. Oncolytic adenoviruses are a possible solution to treatment resistance in PDAC due to their ability to elicit lymphocyte trafficking and epitope spreading. Herein, we tested if an oncolytic adenovirus encoding a variant interleukin-2 molecule (Ad5/3-E2F-d24-vIL2), could enable immune checkpoint inhibitor (ICI) therapy in PDAC when combined with chemotherapy. Rationale for Ad5/3-E2F-d24-vIL2 was tested in vitro, where increase in programmed death ligand 1 (PD-L1) expression was seen after virotherapy and chemotherapy. Expression of other B7 family proteins was characterized in mono- and co-culture settings of cancer cells, fibroblasts, and macrophages. The combination therapy of virotherapy, chemotherapy and ICI was characterized in freshly resected ex vivo pancreatic tumor samples. Combination of ICI with virotherapy showed increased interferon and chemokine production in samples, with expansion of cytotoxic CD8 + T cells seen by flow cytometry. In vivo evaluation of the triple combination therapy in a Syrian hamster model showed improved tumor growth control and overall survival, with concurrent increase in intratumoral lymphocytes during therapy. Animals cured with the therapy showed resistance to re-challenge with the same cell line, supportive of successful generation of anti-tumor immunity in the animals. The combination treatment of Ad5/3-E2F-d24-vIL2, chemotherapy, and checkpoint inhibition is a promising treatment modality to tackle treatment resistance in PDAC. |
| format | Article |
| id | doaj-art-cf9a3df20b9d4dc4a68df7b1729e8f89 |
| institution | OA Journals |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-cf9a3df20b9d4dc4a68df7b1729e8f892025-08-20T02:06:22ZengSpringerCancer Immunology, Immunotherapy1432-08512025-06-0174711310.1007/s00262-025-04072-6Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer modelsSanteri A. Pakola0Nea Ojala1Tatiana V. Kudling2James H. A. Clubb3Elise Jirovec4Mirte van der Heijden5Victor Arias6Lyna Haybout7Saru Basnet8Susanna Grönberg-Vähä-Koskela9Dafne C. A. Quixabeira10Joao M. Santos11Victor Cervera-Carrascon12Otto Hemminki13Anna Kanerva14Harri Mustonen15Pauli Puolakkainen16Hanna Seppänen17Akseli Hemminki18Cancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiDepartment of Surgery, Translational Cancer Medicine Research Program and ICAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University HospitalDepartment of Surgery, Translational Cancer Medicine Research Program and ICAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University HospitalDepartment of Surgery, Translational Cancer Medicine Research Program and ICAN Digital Precision Cancer Medicine Flagship, University of Helsinki and Helsinki University HospitalCancer Gene Therapy Group, Translational Immunology Research Program, Faculty of Medicine, University of HelsinkiAbstract Pancreatic ductal adenocarcinoma (PDAC) is a cancer with dismal prognosis due to resistance to most current therapies. Although immunotherapy has improved the treatment of many solid cancers, pancreatic cancer remains resistant to immunotherapy due to immunosuppressive tumor microenvironment, limited lymphocyte infiltration and lack of neoantigens. Oncolytic adenoviruses are a possible solution to treatment resistance in PDAC due to their ability to elicit lymphocyte trafficking and epitope spreading. Herein, we tested if an oncolytic adenovirus encoding a variant interleukin-2 molecule (Ad5/3-E2F-d24-vIL2), could enable immune checkpoint inhibitor (ICI) therapy in PDAC when combined with chemotherapy. Rationale for Ad5/3-E2F-d24-vIL2 was tested in vitro, where increase in programmed death ligand 1 (PD-L1) expression was seen after virotherapy and chemotherapy. Expression of other B7 family proteins was characterized in mono- and co-culture settings of cancer cells, fibroblasts, and macrophages. The combination therapy of virotherapy, chemotherapy and ICI was characterized in freshly resected ex vivo pancreatic tumor samples. Combination of ICI with virotherapy showed increased interferon and chemokine production in samples, with expansion of cytotoxic CD8 + T cells seen by flow cytometry. In vivo evaluation of the triple combination therapy in a Syrian hamster model showed improved tumor growth control and overall survival, with concurrent increase in intratumoral lymphocytes during therapy. Animals cured with the therapy showed resistance to re-challenge with the same cell line, supportive of successful generation of anti-tumor immunity in the animals. The combination treatment of Ad5/3-E2F-d24-vIL2, chemotherapy, and checkpoint inhibition is a promising treatment modality to tackle treatment resistance in PDAC.https://doi.org/10.1007/s00262-025-04072-6Oncolytic virusAdenovirus, Pancreatic cancerImmunotherapyPD-L1Checkpoint inhibitor |
| spellingShingle | Santeri A. Pakola Nea Ojala Tatiana V. Kudling James H. A. Clubb Elise Jirovec Mirte van der Heijden Victor Arias Lyna Haybout Saru Basnet Susanna Grönberg-Vähä-Koskela Dafne C. A. Quixabeira Joao M. Santos Victor Cervera-Carrascon Otto Hemminki Anna Kanerva Harri Mustonen Pauli Puolakkainen Hanna Seppänen Akseli Hemminki Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models Cancer Immunology, Immunotherapy Oncolytic virus Adenovirus, Pancreatic cancer Immunotherapy PD-L1 Checkpoint inhibitor |
| title | Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models |
| title_full | Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models |
| title_fullStr | Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models |
| title_full_unstemmed | Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models |
| title_short | Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models |
| title_sort | oncolytic adenovirus encoding variant interleukin 2 combined with chemotherapy enables pd l1 inhibition in pancreatic cancer models |
| topic | Oncolytic virus Adenovirus, Pancreatic cancer Immunotherapy PD-L1 Checkpoint inhibitor |
| url | https://doi.org/10.1007/s00262-025-04072-6 |
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