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Combination treatment with hypofractionated radiotherapy plus IL-2/anti-IL-2 complexes and its theranostic evaluation.
- Source :
-
Journal for immunotherapy of cancer [J Immunother Cancer] 2019 Feb 26; Vol. 7 (1), pp. 55. Date of Electronic Publication: 2019 Feb 26. - Publication Year :
- 2019
-
Abstract
- Background: Immunogenic radiotherapy (RT) can act synergistically with immune checkpoint blockers (ICBs). However, alternatives are needed for non-responding patients and those with pre-existing or ICB-induced autoimmune symptoms. Combination of RT with IL-2 could be an alternative. But IL-2 has a short half-life, and, by binding to its high-affinity receptor, it strongly stimulates immunosuppressive CD4+ Tregs and seems to promote potentially life-threatening vascular leakage. IL-2/anti-IL-2 complexes (IL-2c), which bind to the low-affinity receptor, have been reported to circumvent these disadvantages but they have not yet been thoroughly tested in conjunction with radiotherapy.<br />Methods: We evaluated, in three mouse models, the antitumoral effects induced by hypofractionated RT (hRT) plus IL-2c. We also used non-invasive imaging with a newly developed PET tracer based on therapeutically active IL-2c and a PD-L1 PET tracer for the theranostic evaluation of the treatment and its side effects.<br />Results: Treatment of mice bearing established B16 melanomas with hRT + IL-2c was superior to hRT + uncomplexed IL-2 or hRT alone; IL-2c alone was not effective. hRT + IL-2c was also synergistic in mice bearing C51 colon carcinomas or 4T1 mammary carcinomas. The better antitumor response correlated with increased tumor-specific CD8+ T cells and NK cells, but not CD4+ Tregs, in the irradiated tumor and in lymphoid organs. With the new PET tracer, we visualized the whole-body distribution of IL-2c and the bound receptors in naïve mice and tumor-bearing mice. Surprisingly, the tumor uptake was non-specific and only moderate. This prompted experiments demonstrating that specific IL-2c binding in the tumor is limited by IL-2 secreted by tumor-resident effector cells and that extratumorally expanded T and NK cells can infiltrate the irradiated tumor, which suggests that systemic immune activation considerably contributed to the reduction of tumor growth. Lastly, we show that a side effect of IL-2c treatment - a quite dramatic non-specific expansion of CD8+ T and NK cells - is only transient, and we visualized the associated splenomegaly as well as side effects on liver and lung by contrast-enhanced CT and PD-L1 PET.<br />Conclusions: Our results show that the combination of immunogenic RT with IL-2c that are directed towards the low-affinity IL-2 receptor can be synergistic and more effective than the combination with uncomplexed IL-2. In addition, our theranostic evaluation provided insights into the mechanism of action and the side effects of IL-2c treatment.
- Subjects :
- Adoptive Transfer
Animals
B7-H1 Antigen genetics
B7-H1 Antigen metabolism
Biomarkers
Cell Line, Tumor
Combined Modality Therapy
Disease Models, Animal
Drug Synergism
Humans
Immunologic Factors pharmacology
Immunophenotyping
Killer Cells, Natural drug effects
Killer Cells, Natural immunology
Killer Cells, Natural metabolism
Mice
Neoplasms diagnostic imaging
Neoplasms etiology
Positron Emission Tomography Computed Tomography
Positron-Emission Tomography
Species Specificity
T-Lymphocyte Subsets drug effects
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
Xenograft Model Antitumor Assays
Antibodies, Monoclonal pharmacology
Interleukin-2 pharmacology
Neoplasms pathology
Neoplasms therapy
Radiation Dose Hypofractionation
Subjects
Details
- Language :
- English
- ISSN :
- 2051-1426
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal for immunotherapy of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 30808414
- Full Text :
- https://doi.org/10.1186/s40425-019-0537-9