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Radiotherapy in Combination With Cytokine Treatment.

ABSTRACT: Radiotherapy (RT) plays an important role in the management of cancer patients. RT is used in more than 50% of patients during the course of their disease in a curative or palliative setting. In the past decades it became apparent that the abscopal effect induced by RT might be dependent on the activation of immune system, and that the induction of immunogenic cancer cell death and production of danger-associated molecular patterns from dying cells play a major role in the radiotherapy-mediated anti-tumor efficacy. Therefore, the combination of RT and immunotherapy is of a particular interest that is reflected in designing clinical trials to treat patients with various malignancies. The use of cytokines as immunoadjuvants in combination with RT has been explored over the last decades as one of the immunotherapeutic combinations to enhance the clinical response to anti-cancer treatment. Here we review mainly the data on the efficacy of IFN-?, IL-2, IL-2-based immunocytokines, GM-CSF, and TNF-? used in combinations with various radiotherapeutic techniques in clinical trials. Moreover, we discuss the potential of IL-15 and its analogs and IL-12 cytokines in combination with RT based on the efficacy in preclinical mouse tumor models.

SUBMITTER: Palata O

PROVIDER: S-EPMC6538686 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Radiotherapy in Combination With Cytokine Treatment.

Palata Ondrej O Hradilova Podzimkova Nada N Nedvedova Eva E Umprecht Alexandra A Sadilkova Lenka L Palova Jelinkova Lenka L Spisek Radek R Adkins Irena I

Frontiers in oncology 20190522

Radiotherapy (RT) plays an important role in the management of cancer patients. RT is used in more than 50% of patients during the course of their disease in a curative or palliative setting. In the past decades it became apparent that the abscopal effect induced by RT might be dependent on the activation of immune system, and that the induction of immunogenic cancer cell death and production of danger-associated molecular patterns from dying cells play a major role in the radiotherapy-mediated ...[more]

PMID: 31179236

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Project description:BackgroundImmunogenic 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.MethodsWe 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.ResultsTreatment 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.ConclusionsOur 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.

Dataset Information

Radiotherapy in Combination With Cytokine Treatment.

Publications

Radiotherapy in Combination With Cytokine Treatment.

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