Carbon ion irradiation enhances the antitumor efficacy of dual immune checkpoint blockade therapy both for local and distant sites in murine osteosarcoma

Takahashi, Yutaka; Yasui, Toshimichi; Minami, Kazumasa; Tamari, Keisuke; Hayashi, Kazuhiko; Otani, Keisuke; Seo, Yuji; Isohashi, Fumiaki; Koike, Masahiko; Ogawa, Kazuhiko

doi:10.18632/oncotarget.26551

Cited by 60 publications

(53 citation statements)

References 53 publications

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“…First, an increased second tumor rejection was observed following injection of-pre-treated dendritic cells [ 296 , 297 , 298 ]. Second, reduced lung metastasis were measured after combination of C-ions with anti-CTLA4 and anti-PD-1 checkpoint inhibitors [ 299 ], and the effect was stronger when using C-ions than X-rays [ 300 ]. These results should be confirmed and can drive clinical trials.…”

Section: Molecular Radiobiologymentioning

confidence: 99%

Carbon Ion Radiobiology

Tinganelli

Durante

2020

Cancers

156

134

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Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy are irradiated with protons, which have physical advantages compared to X-rays but a similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue) and be exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and a reduced oxygen enhancement ratio compared to X-rays. Some radiobiological properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different “drug” in oncology, and may elicit favorable responses such as an increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results.

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Section: Molecular Radiobiologymentioning

confidence: 99%

Carbon Ion Radiobiology

Tinganelli

Durante

2020

Cancers

156

134

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“…Another tumour-transplanted mouse analysis of combined RT with anti-PD-L1 antibody treatment demonstrated that the number of MDSCs and Tregs in the tumour decreased, whereas the number of CD8-positive T cells increased, suggesting that the control of immunosuppression by combined treatment can contribute to the inhibition of tumour growth [58]. Furthermore, recently, Takahashi et al reported that carbon-ion radiotherapy combined with anti-PD-L1 antibody and anti-CTLA-4 antibody delayed tumour growth not only in the irradiated tumours but also in the unirradiated tumours [59]. It is important to note that they used both anti-CTLA-4 as well as anti-PD-L1 antibodies.…”

Section: Preclinical Evidences On Combined Therapymentioning

confidence: 99%

Rationale of combination of anti-PD-1/PD-L1 antibody therapy and radiotherapy for cancer treatment

2020

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Significant technological advances in radiotherapy have been made in the past few decades. High-precision radiotherapy has recently become popular and is contributing to improvements in the local control of the irradiated target lesions and the reduction of adverse effects. Accordingly, for long-term survival, the importance of systemic cancer control, including at non-irradiated sites, is growing. Toward this challenge, the treatment methods in which anti-PD-1/PD-L1 antibodies that exert systemic effects by restoring anti-tumour immunity are combined with radiotherapy has attracted attention in recent years. Previous studies have reported the activation of anti-tumour immunity by radiotherapy, which simultaneously elevates PD-L1 expression, suggesting a potential for combination therapy. Radiotherapy induces so-called 'immunogenic cell death', which involves cell surface translocation of calreticulin and extracellular release of high-mobility group protein box 1 (HMGB-1) and adenosine-5′-triphosphate (ATP). Furthermore, radiotherapy causes immune activation via MHC class I upregulation and cGAS-STING pathway. In contrast, induction of immunosuppressive lymphocytes and the release of immunosuppressive cytokines and chemokines by radiotherapy contribute to immunosuppressive reactions. In this article, we review immune responses induced by radiotherapy as well as previous reports to support the rationale of combination of radiotherapy and anti-PD-1/PD-L1 antibodies. A number of preclinical and clinical studies have shown the efficacy of radiotherapy combined with immune checkpoint inhibition, hence combination therapy is considered to be an important future strategy for cancer treatment.

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“…In this study, increased CD8 + granzyme B + T cells and CD4 + T cells in nonirradiated areas were also found after combination treatment. 113 Additionally, in gliomabearing mice treated with combinations of anti-PD-1, anti-TIM-3 or local 10 Gy stereotactic radiation, dual therapies increased median survival modestly over single agents. Interestingly, triple-therapy anti-TIM-3/anti-PD-1/SRS resulted in overall survival of 100%.…”

Section: Other Cancersmentioning

confidence: 99%

Enhancing the efficacy of immunotherapy using radiotherapy

et al. 2020

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Recent clinical breakthroughs in cancer immunotherapy, especially with immune checkpoint blockade, offer great hope for cancer sufferersand have greatly changed the landscape of cancer treatment. However, whilst many patients achieve clinical responses, others experience minimal benefit or do not respond to immune checkpoint blockade at all. Researchers are therefore exploring multimodal approaches by combining immune checkpoint blockade with conventional cancer therapies to enhance the efficacy of treatment. A growing body of evidence from both preclinical studies and clinical observations indicates that radiotherapy could be a powerful driver to augment the efficacy of immune checkpoint blockade, because of its ability to activate the antitumor immune response and potentially overcome resistance. In this review, we describe how radiotherapy induces DNA damage and apoptosis, generates immunogenic cell death and alters the characteristics of key immune cells in the tumor microenvironment. We also discuss recent preclinical work and clinical trials combining radiotherapy and immune checkpoint blockade in thoracic and other cancers. Finally, we discuss the scheduling of immune checkpoint blockade and radiotherapy, biomarkers predicting responses to combination therapy, and how these novel data may be translated into the clinic.

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Carbon ion irradiation enhances the antitumor efficacy of dual immune checkpoint blockade therapy both for local and distant sites in murine osteosarcoma

Cited by 60 publications

References 53 publications

Carbon Ion Radiobiology

Carbon Ion Radiobiology

Rationale of combination of anti-PD-1/PD-L1 antibody therapy and radiotherapy for cancer treatment

Enhancing the efficacy of immunotherapy using radiotherapy

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