Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination

Gong, Jun; Le, Thang Q.; Massarelli, Erminia; Hendifar, Andrew Eugene; Tuli, Richard

doi:10.1186/s40425-018-0361-7

Cited by 148 publications

(118 citation statements)

References 169 publications

(114 reference statements)

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“…Further, concurrent combination improved response rate and abscopal effects in patient with metastatic melanoma [85,86]. In this manner, a number of other retrospective case series support the notion of a combination strategy of RT and anti-PD-1/PD-L1 antibody therapy, including both concurrent and sequential use [87]. Taken together, although the precise mechanisms contributing to better prognosis are still unclear, RT may sustainably maintain the host immunity in favourable immune environments with anti-PD-1/PD-L1 antibody treatment as well as temporary immune response.…”

Section: Clinical and Translational Evidences On Combined Therapymentioning

confidence: 95%

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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Section: Clinical and Translational Evidences On Combined Therapymentioning

confidence: 95%

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

2020

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“…Recent emerging data indicate that combining PD-L1 inhibitors with other therapies including chemotherapy, radiotherapy and immunotherapy might be more beneficial to cure cancer patients [26][27][28] and we already have been studied that ionizing radiation was efficient modality to trigger NK cell-mediated immune responses [29]. Therefore, we evaluated the efficacy on NK cellmediated anticancer immune responses by the combination with PD-L1 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Blocking of programmed death ligand 1 enhances natural killer cell-mediated immunity against malignant melanoma cells

Lee

Heo

Choi

et al. 2020

Preprint

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Background Since ionizing radiation has showed the dramatic effect to kill the cancer cells by direct DNA damage as well as triggering anti-cancer immune responses through release of various tumor antigens and induction of NK activating molecules, it has been used for long time to treat many cancer patients including patients with melanoma. However, it has been known that radiotherapy might promote the remnant cancer cells to escape immune system. One of the suggested ways is induction of a ligand for programmed death-1 (PD-L1) after radiotherapy in head and neck cancer, bladder cancer and lung cancer cells which engages the receptor, programmed death-1 (PD-1) in immune cells. PD-1/PD-L1 axis transduces the inhibitory signal and suppresses the adaptive immunity in T cells. However, their role in innate immunity remains poorly understood. Therefore, we investigated whether ionizing radiation could change the expression of PD-L1/2 in malignant melanoma cells and the receptor, PD-1, in NK-92 cells. Results Surface PD-L1/2 levels on melanoma cells were increased by ionizing radiation in a dose-dependent manner but the level of PD-L1 was not changed significantly in NK-92 cells. Radiation-induced PD-L1/2 suppressed the activity of the NK-92 cells against melanoma cells despite of upregulation of NKG2D ligands. Furthermore, activated NK cells had high level of PD-1 and could not kill PD-L1/2+ melanoma cells effectively. When we used PD-L1 inhibitor or silenced PD-L1 gene to inhibit PD-1/PD-L1 axis, they reversed the activity of the suppressed NK cells. Conclusions Through these results, we supposed that PD-1/PD-L1 blockade could enhance the immune responses of NK cells against melanoma cells after radiotherapy and might overcome the PD-L1 mediated radioresistance of cancer cells.

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“…Ionizing radiation (RT) therapy induces IFN-γ, type I IFN production and PD-1/PD-L1 expression on tumor cells 19 . When combined with cisplatin, the immunogenic effect of RT is further potentiated via calreticulin exposure, release of ATP, induction of programmed death receptor 1-ligand (PD-L1) and highmobility protein box-1 (HMGB-1) 20,21 .…”

Section: Rationale For Immunotherapy and Platinum-sensitized Radiothementioning

confidence: 99%

A Phase 2 Study of Combined Chemo-Immunotherapy with Cisplatin-Pembrolizumab and Radiation for Unresectable Vulvar Squamous Cell Carcinoma

Yeku

Russo

Lee

et al. 2020

Preprint

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Purpose: Unresectable or metastatic vulva cancer has relatively poor outcomes despite chemotherapy-sensitized radiation therapy and combination cytotoxic therapy. Despite the virus-associated and immunogenic nature of this disease, novel immunotherapy options that exploit this advantage are currently lacking. Platinum agents such as cisplatin have been shown to prime dendritic cells for T-cell costimulation, promote downregulation of inhibitory checkpoint molecules, and sensitize tumor cells to cytotoxic T-cell killing. Radiation therapy has also been shown to promote immunogenetic cell death as monotherapy and in combination with cisplatin. In combination with pembrolizumab, cisplatin-sensitized radiation is hypothesized to increase overall response rates and recurrence-free survival in patients with vulva cancer, via induction of an anti-tumor inflammatory response.Methods: We propose a single-arm phase II clinical trial of pembrolizumab combined with cisplatin-sensitized radiation therapy for women with unresectable, locally advanced, or metastatic vulva cancer. The first three patients with locally advanced or unresectable disease will receive cycle 1 of pembrolizumab followed by a break and resumption of pembrolizumab at cycle 4 and as part of a safety cohort. All other patients, including the fourth patient with locally advanced/unresectable disease, will receive weekly cisplatin and pembrolizumab every 3 weeks, concurrently with daily radiation therapy. Following the completion of Cis-RT, patients will continue pembrolizumab maintenance for a total of 12 cycles. Archived tissue will be used for HPV status, MSI status, PD-L1, and TIL stratification post-hoc. Imaging will be performed at baseline and every 3 cycles (21-day cycles) as per standard-of-care. Laboratory analysis will occur on the first day of each cycle. Discussion: The combination of cisplatin-sensitized radiation and immune checkpoint blockade has not been evaluated in the upfront setting for vulvar cancer. In this rare malignancy, there are limited interventional clinical trials. This trial is designed to be as accessible as possible by allowing patients to receive cisplatin and radiation locally according to accepted standard-of-care while receiving pembrolizumab and adverse event monitoring at a centralized site. A robust suite of translational correlative studies has also been built into the trial to evaluate tumor-directed immune activation. Trial registration: NCT04430699

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Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination

Cited by 148 publications

References 169 publications

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

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

Blocking of programmed death ligand 1 enhances natural killer cell-mediated immunity against malignant melanoma cells

A Phase 2 Study of Combined Chemo-Immunotherapy with Cisplatin-Pembrolizumab and Radiation for Unresectable Vulvar Squamous Cell Carcinoma

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