Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19–IL2 cures poorly immunogenic tumors when combined with radiotherapy
| العنوان: | Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19–IL2 cures poorly immunogenic tumors when combined with radiotherapy |
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| المؤلفون: | Ludwig Dubois, Jan Theys, Dario Neri, Natasja G. Lieuwes, Alexander M A van der Wiel, Ala Yaromina, R. Biemans, Veronica Olivo Pimentel, Relinde I Y Lieverse, Philippe Lambin, Damiënne Marcus |
| المساهمون: | Precision Medicine, RS: GROW - R2 - Basic and Translational Cancer Biology, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy |
| المصدر: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 3 (2021) Journal for ImmunoTherapy of Cancer, 9 (3) Journal for ImmunoTherapy of Cancer, 9(3):001764. BioMed Central Ltd Journal for ImmunoTherapy of Cancer Journal for Immunotherapy of Cancer |
| بيانات النشر: | BMJ Publishing Group, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, Lung Neoplasms, IMMUNOCYTOKINE NHS-IL12, medicine.medical_treatment, ANTITUMOR-ACTIVITY, CD8-Positive T-Lymphocytes, B7-H1 Antigen, CHECKPOINT INHIBITOR, Carcinoma, Lewis Lung, Immunomodulating Agents, 0302 clinical medicine, Immunology and Allergy, Cytotoxic T cell, CTLA-4 Antigen, Immune Checkpoint Inhibitors, RC254-282, Clinical/Translational Cancer Immunotherapy, Mice, Inbred BALB C, 0303 health sciences, Abscopal effect, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Chemoradiotherapy, Primary tumor, CANCER, Tumor Burden, 3. Good health, Killer Cells, Natural, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Molecular Medicine, immunotherapy, Signal Transduction, PD-L1, Recombinant Fusion Proteins, Immunology, MECHANISMS, Memory T Cells, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, Cell Line, Tumor, medicine, Animals, tumor microenvironment, COMBINATION, radiotherapy, 030304 developmental biology, Pharmacology, Tumor microenvironment, business.industry, CTLA-4 BLOCKADE, Lewis lung carcinoma, Immunotherapy, medicine.disease, Coculture Techniques, Immune checkpoint, Mice, Inbred C57BL, ANTIBODY, Cancer research, T-CELLS, business, Immunologic Memory |
| الوصف: | BackgroundPoorly immunogenic tumors are hardly responsive to immunotherapies such as immune checkpoint blockade (ICB) and are, therefore, a therapeutic challenge. Combination with other immunotherapies and/or immunogenic therapies, such as radiotherapy (RT), could make these tumors more immune responsive. We have previously shown that the immunocytokine L19–IL2 combined with single-dose RT resulted in 75% tumor remission and a 20% curative abscopal effect in the T cell-inflamed C51 colon carcinoma model. This treatment schedule was associated with the upregulation of inhibitory immune checkpoint (IC) molecules on tumor-infiltrating T cells, leading to only tumor growth delay in the poorly immunogenic Lewis lung carcinoma (LLC) model.MethodsWe aimed to trigger curative therapeutic responses in three tumor models (LLC, C51 and CT26) by “pushing the accelerator” of tumor immunity with L19–IL2 and/or “releasing the brakes” with ICB, such as antibodies directed against cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), combined with single-dose RT (10 Gy or 5 Gy). Primary tumor endpoint was defined as time to reach four times the size of tumor volume at start of treatment (4T×SV). Multivariate analysis of 4T×SV was performed using the Cox proportional hazards model comparing each treatment group with controls. Causal involvement of T and natural killer (NK) cells in the anti-tumor effect was assessed by in vivo depletion of T, NK or both cell populations. Immune profiling was performed using flow cytometry on single cell suspensions from spleens, bone marrow, tumors and blood.ResultsCombining RT, anti-PD-L1 and L19–IL2 cured 38% of LLC tumors, which was both CD8+ T and NK cell dependent. LLC tumors were resistant to RT +anti-PD-L1 likely explained by the upregulation of other IC molecules and increased T regulatory cell tumor infiltration. RT+L19–IL2 outperformed RT+ICB in C51 tumors; effects were comparable in CT26 tumors. Triple combinations were not superior to RT+L19–IL2 in both these models.ConclusionsThis study demonstrated that combinatorial strategies rationally designed on biological effects can turn immunotherapy-resistant tumors into immunologically responsive tumors. This hypothesis is currently being tested in the international multicentric randomized phase 2 trial: ImmunoSABR (NCT03705403). |
| وصف الملف: | application/application/pdf |
| اللغة: | English |
| تدمد: | 2051-1426 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bae4375d17de5a2aca6741c0b19a0e56 https://jitc.bmj.com/content/9/3/e001764.full |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bae4375d17de5a2aca6741c0b19a0e56 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20511426 |
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