Immune checkpoint blockade in small cell lung cancer: is there a light at the end of the tunnel?

Paglialunga, Luca; Salih, Zena; Ricciuti, Biagio; Califano, Raffaele

doi:10.1136/esmoopen-2015-000022

Cited by 18 publications

(17 citation statements)

References 36 publications

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“…However, despite having one of the highest mutational burdens, small cell lung cancer (SCLC) is often accompanied by relatively high immunosuppression with low levels of T-cell infi ltration and reduced antigen presentation (9)(10)(11). Consistent with this, clinical trials investigating PD-1 or PD-L1 blockade in patients with SCLC have shown low overall response rates ( 12,13 ).…”

Section: Introductionmentioning

confidence: 95%

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

et al. 2019

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Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) signifi cantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the antitumor effect of PD-L1 blockade and augmented cytotoxic T-cell infi ltration in multiple immunocompetent SCLC in vivo models. CD8 + T-cell depletion reversed the antitumor effect, demonstrating the role of CD8 + T cells in combined DDR-PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T lymphocytes. Knockdown of cGAS and STING successfully reversed the antitumor effect of combined inhibition of DDR and PD-L1. Our results defi ne previously unrecognized innate immune pathway-mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC. SIGNIFICANCE: Our results defi ne previously unrecognized immunomodulatory functions of DDR inhibitors and suggest that adding PARP or CHK1 inhibitors to ICB may enhance treatment effi cacy in patients with SCLC. Furthermore, our study supports a role of innate immune STING pathway in DDR-mediated antitumor immunity in SCLC.

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Section: Introductionmentioning

confidence: 95%

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

et al. 2019

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“…CTLA-4 was the first immune checkpoint receptor to be targeted by a therapeutic agent 26. Monoclonal antibodies against CTLA-4 (ipilimumab and tremelimumab) are designed to prevent the interaction between CTLA-4 and its ligands (CD80/CD86).…”

Section: Introductionmentioning

confidence: 99%

<p>Immune checkpoint inhibitors for small cell lung cancer: opportunities and challenges</p>

Regzedmaa¹,

Zhang²,

Liu³

2019

OTT

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Lung cancer is the most common cancer and the leading cause of cancer death worldwide, with an estimated 2.1 million new cases and 1.8 million deaths in 2018. Although small cell lung cancer (SCLC) is the most aggressive type of lung cancer, it shows high response rates to chemotherapy in early lines of therapy. Unfortunately, it is associated with rapid recurrence and relatively poor prognosis. Over the last few years, considerable progress has been made in cancer immunotherapy. One of the most promising ways to activate therapeutic antitumor immunity is via blockade of immune checkpoints, such as cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1). Immune checkpoint inhibitors show promise as SCLC therapeutics. The overall expectation for immuno-oncology is high, and the outcomes of trials will hopefully reveal a variety of treatment options for SCLC patients. In this review, we discuss the discovery of new immune inhibitory and stimulatory pathways and rational combination strategies to explain the role of immunotherapy in SCLC and its future opportunities and challenges.

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“…They fall into the broad categories of topoisomerase inhibitors (etoposide, teniposide, doxorubicin, topotecan, irinotecan), platinum agents (cisplatin, carboplatin), vinca alkaloids (vincristine, vinorelbine), and alkylating agents (cyclophosphamide, temozolomide). The role of immunotherapy (such as pembrolizumab or nivolumab with ipilumimab) is beginning to emerge for SCLC [ 92 , 93 ]. However, immunotherapy has not been systematically studied in SCLC CNS metastases.…”

Section: Introductionmentioning

confidence: 99%

State-of-the-art considerations in small cell lung cancer brain metastases

et al. 2017

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BackgroundSmall cell lung cancer (SCLC) frequently leads to development of brain metastases. These unfortunately continue to be associated with short survival. Substantial advances have been made in our understanding of the underlying biology of disease. This understanding on the background of previously evaluated and currently utilized therapeutic treatments can help guide the next steps in investigations into this disease with the potential to influence future treatments.DesignA comprehensive review of the literature covering epidemiology, pathophysiology, imaging characteristics, prognosis, and therapeutic management of SCLC brain metastases was performed.ResultsSCLC brain metastases continue to have a poor prognosis. Both unique aspects of SCLC brain metastases as well as features seen more universally across other solid tumor brain metastases are discussed. Systemic therapeutic studies and radiotherapeutic approaches are reviewed.ConclusionsA clearer understanding of SCLC brain metastases will help lay the framework for studies which will hopefully translate into meaningful therapeutic options for these patients.

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Immune checkpoint blockade in small cell lung cancer: is there a light at the end of the tunnel?

Cited by 18 publications

References 36 publications

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

<p>Immune checkpoint inhibitors for small cell lung cancer: opportunities and challenges</p>

State-of-the-art considerations in small cell lung cancer brain metastases

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