Journal Article

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

Lieverse, Relinde IY, Olivo Pimentel, Veronica, van der Wiel, Alexander MA, Yaromina, Ala, Biemans, Rianne, Marcus, Damiënne, Lambin, Philippe, Dubois, Ludwig J, Lieuwes, Natasja G, Neri, Dario, Theys, Jan

2021

Overview

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).

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Animals / Antibodies / Antigens / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - metabolism / Cancer / Cancer therapies / Carcinoma, Lewis Lung - immunology / Carcinoma, Lewis Lung - metabolism / Carcinoma, Lewis Lung - pathology / Carcinoma, Lewis Lung - therapy / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line, Tumor / Chemoradiotherapy / Clinical/Translational Cancer Immunotherapy / Coculture Techniques / Colon / Colonic Neoplasms - immunology / Colonic Neoplasms - metabolism / Colonic Neoplasms - pathology / Colonic Neoplasms - therapy / Colorectal cancer / CTLA-4 Antigen - antagonists & inhibitors / CTLA-4 Antigen - metabolism / Cytokines / Cytotoxicity / Experiments / Flow cytometry / Immune Checkpoint Inhibitors - pharmacology / Immunologic Memory - drug effects / Immunomodulating Agents - pharmacology / Immunotherapy / Killer Cells, Natural - drug effects / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Lung cancer / Lung Neoplasms - immunology / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Lung Neoplasms - therapy / Lymphocytes / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Memory T Cells - drug effects / Memory T Cells - immunology / Memory T Cells - metabolism / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Radiation therapy / Recombinant Fusion Proteins - pharmacology / Response rates / Signal Transduction / Tumor Burden - drug effects / Tumor Microenvironment / Tumors