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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
- Source :
- 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
- Publication Year :
- 2021
- Publisher :
- BMJ Publishing Group, 2021.
-
Abstract
- 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).
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20511426
- Volume :
- 9
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal for ImmunoTherapy of Cancer
- Accession number :
- edsair.doi.dedup.....bae4375d17de5a2aca6741c0b19a0e56