PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment
Background More efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immu...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e009832.full |
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| author | Pedro J Romero Sara Labiano Gregory Verdeil Christian Klein Pablo Umana Tania Wyss Christine Trumpfheller Marie-Catherine Vozenin Céline Godfroid Jackeline Romero Vincent Roh Genrich V Tolstonog Chia-Hsien Chuang Andrea Kelemen Laura Codarri Deak |
| author_facet | Pedro J Romero Sara Labiano Gregory Verdeil Christian Klein Pablo Umana Tania Wyss Christine Trumpfheller Marie-Catherine Vozenin Céline Godfroid Jackeline Romero Vincent Roh Genrich V Tolstonog Chia-Hsien Chuang Andrea Kelemen Laura Codarri Deak |
| author_sort | Pedro J Romero |
| collection | DOAJ |
| description | Background More efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immunotherapy combining hypofractionated radiotherapy (HRT) with muPD1-IL2v immunocytokine and muFAP-CD40 bispecific antibody.Methods We evaluated the changes in the lung immune microenvironment at multiple timepoints following combination therapies and investigated their underlying antitumor mechanisms. Additionally, we analyzed the tumor clonal heterogeneity upon the combination treatments to explore potential mechanisms associated with the lack of complete response.Results The combination of HRT with muPD1-IL2v had a potent antitumor effect and increased survival in the SV2-OVA lung cancer model. Importantly, this combination therapy was devoid of measurable toxicity. It induced remodeling of the immune contexture through the increase of CD8+ T and natural killer (NK) cells. The addition of muFAP-CD40 to the combination treatment further increased infiltrating CD8+ T cells, expressing high levels of effector molecules, both in the periphery and core tumor regions. An accumulation of CD8+ PD-1+ TOX+ (exhausted) T cells, already at the ‘early’ timepoint, is consistent with the limited clinical benefits provided by the various combination treatments in this model. The study of the clonal dynamics of tumor cells during disease progression and therapy highlighted a clonal selection upon HRT+muPD1-IL2v therapy.Conclusions We demonstrated that HRT+muPD1-IL2v combination is a potent therapeutic strategy to delay tumor growth and increase survival in a metastatic lung cancer model, but additional studies are required to completely understand the resistance mechanisms associated with the lack of complete response in this model. |
| format | Article |
| id | doaj-art-4775df2d3a2b495981e5fc9f2dbd2d1c |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4775df2d3a2b495981e5fc9f2dbd2d1c2025-02-03T08:30:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-009832PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironmentPedro J Romero0Sara Labiano1Gregory Verdeil2Christian Klein3Pablo Umana4Tania Wyss5Christine Trumpfheller6Marie-Catherine Vozenin7Céline Godfroid8Jackeline Romero9Vincent Roh10Genrich V Tolstonog11Chia-Hsien Chuang12Andrea Kelemen13Laura Codarri Deak14Route de la Corniche 3B, Novigenix SA, 1066, Epalinges, Switzerland5Clínica Universidad de Navarra, Pamplona, Navarra, SpainDepartment of Oncology, University of Lausanne, Epalinges, SwitzerlandRoche Glycart AG, Schlieren, Switzerland6Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Zurich (RICZ), Schlieren, SwitzerlandDepartment of Oncology, University of Lausanne, Epalinges, SwitzerlandRoche Glycart AG, Schlieren, SwitzerlandSector of Radiobiology Applied to Radiotherapy, Radiation Oncology Service, Geneva University Hospital, Geneva, SwitzerlandDepartment of Oncology, University of Lausanne, Epalinges, SwitzerlandDepartment of Radiation Oncology, CHUV, Lausanne, SwitzerlandTDS-facility, SIB, Lausanne, SwitzerlandDepartment of Otolaryngology-Head and Neck Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandDepartment of Otolaryngology-Head and Neck Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandDepartment of Otolaryngology-Head and Neck Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandRoche Glycart AG, Schlieren, SwitzerlandBackground More efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immunotherapy combining hypofractionated radiotherapy (HRT) with muPD1-IL2v immunocytokine and muFAP-CD40 bispecific antibody.Methods We evaluated the changes in the lung immune microenvironment at multiple timepoints following combination therapies and investigated their underlying antitumor mechanisms. Additionally, we analyzed the tumor clonal heterogeneity upon the combination treatments to explore potential mechanisms associated with the lack of complete response.Results The combination of HRT with muPD1-IL2v had a potent antitumor effect and increased survival in the SV2-OVA lung cancer model. Importantly, this combination therapy was devoid of measurable toxicity. It induced remodeling of the immune contexture through the increase of CD8+ T and natural killer (NK) cells. The addition of muFAP-CD40 to the combination treatment further increased infiltrating CD8+ T cells, expressing high levels of effector molecules, both in the periphery and core tumor regions. An accumulation of CD8+ PD-1+ TOX+ (exhausted) T cells, already at the ‘early’ timepoint, is consistent with the limited clinical benefits provided by the various combination treatments in this model. The study of the clonal dynamics of tumor cells during disease progression and therapy highlighted a clonal selection upon HRT+muPD1-IL2v therapy.Conclusions We demonstrated that HRT+muPD1-IL2v combination is a potent therapeutic strategy to delay tumor growth and increase survival in a metastatic lung cancer model, but additional studies are required to completely understand the resistance mechanisms associated with the lack of complete response in this model.https://jitc.bmj.com/content/13/1/e009832.full |
| spellingShingle | Pedro J Romero Sara Labiano Gregory Verdeil Christian Klein Pablo Umana Tania Wyss Christine Trumpfheller Marie-Catherine Vozenin Céline Godfroid Jackeline Romero Vincent Roh Genrich V Tolstonog Chia-Hsien Chuang Andrea Kelemen Laura Codarri Deak PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment Journal for ImmunoTherapy of Cancer |
| title | PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment |
| title_full | PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment |
| title_fullStr | PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment |
| title_full_unstemmed | PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment |
| title_short | PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment |
| title_sort | pd 1 cis targeted il 2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment |
| url | https://jitc.bmj.com/content/13/1/e009832.full |
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