Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors

Hargadon, Kristian M.; Johnson, Coleman E.; Williams, Corey J.

doi:10.1016/j.intimp.2018.06.001

Cited by 937 publications

(757 citation statements)

References 99 publications

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“…13,14 The checkpoint blockade immunotherapies (such as nivolumab and atezolizumab) have been approved by FDA for the treatment of multiple types of cancer. 15,16 In GBM, higher PD-L1 expression has been correlated with poorer patient prognoses, 17 suggesting that PD-L1 does suppress antitumor immunity in some patients. In addition, case reports have indicated that anti-PD-1 therapy is effective for some patients with GBM.…”

Section: Introductionmentioning

confidence: 99%

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Zhou

Zhao

Yang

et al. 2019

Intl Journal of Cancer

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Pevonedistat (MLN4924), a specific NEDD8‐activating enzyme inhibitor, has been considered as a promising treatment for glioblastoma, which is currently in Phase I/II clinical trials. On the other hand, inhibition of neddylation pathway substantially upregulates the expression of T cell negative regulator programmed death‐ligand 1 (PD‐L1), which might account for the potential resistance via evasion of immune surveillance checkpoints. Whether administration of anti‐PD‐L1 enhances the efficacy of pevonedistat through a cytotoxic T cell‐dependent mechanism in glioblastoma needs to be investigated. Here, we report that depletion of neddylation pathway key enzymes markedly elevates PD‐L1 expression in glioblastoma cancer cells. Consistently, neddylation inhibitor pevonedistat significantly enhances PD‐L1 expression in both glioblastoma cancer cell lines and animal models. Mechanistically, pevonedistat increases PD‐L1 mRNA levels mainly through inhibiting Cullin1‐F‐box and WD repeat domain‐containing 7 E3 ligase activity and accumulating c‐MYC proteins, a direct transcriptional activator of PD‐L1 gene expression. In addition, inhibition of Cullin3 activity by pevonedistat also blocks PD‐L1 protein degradation. Importantly, pevonedistat attenuates T cell killing through PD‐L1 induction, and blockade of PD‐L1 restores the sensitivity of pevonedistat‐treated glioblastoma cancer cells to T cell killing. The combination of pevonedistat and anti‐PD‐L1 therapy compared to each agent alone significantly increased the therapeutic efficacy in vivo. Our study demonstrates inhibition of neddylation pathway suppresses cancer‐associated immunity and provides solid evidence to support the combination of pevonedistat and PD‐L1/programmed cell death protein 1 immune checkpoint blockade as a potential therapeutic strategy to treat glioblastoma.

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Section: Introductionmentioning

confidence: 99%

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Zhou

Zhao

Yang

et al. 2019

Intl Journal of Cancer

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“…Monoclonal antibodies that block the interaction between programmed death 1 (PD‐1) and its ligand (PD‐L1) are established treatments for various tumor types . By blocking the immune inhibitory effects induced by this molecular interaction, anti–PD‐1 or anti–PD‐L1 antibodies can reactivate and maintain antitumor immune responses, resulting in therapeutic efficacy . Within oncology, there has been a shift from traditional weight‐based dosing with cytotoxic agents to the use of a flat dose with monoclonal antibodies.…”

mentioning

confidence: 99%

“…1 By blocking the immune inhibitory effects induced by this molecular interaction, anti-PD-1 or anti-PD-L1 antibodies can reactivate and maintain antitumor immune responses, resulting in therapeutic efficacy. 2 Within oncology, there has been a shift from traditional weight-based dosing with cytotoxic agents to the use of a flat dose with monoclonal antibodies. Furthermore, the anti-PD-1 antibodies nivolumab and pembrolizumab were initially approved with weight-based dosing, but the dosing was changed to flat dosing based on exposure-efficacy, exposure-safety, and pharmacokinetic (PK) modeling studies, which showed a similar benefit:risk profile, in addition to subsequent clinical studies of pembrolizumab dosing.…”

mentioning

confidence: 99%

Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma

Novakovic

Wilkins²,

Dai

et al. 2019

Clin Pharma and Therapeutics

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Avelumab, an anti–programmed death‐ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum‐treated urothelial carcinoma, was initially approved with a 10 mg/kg weight‐based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab comparing weight‐based dosing and a flat 800 mg dose, developed using data from 1,827 patients enrolled in 3 clinical trials (NCT01772004, NCT01943461, and NCT02155647). PK metrics were simulated for weight‐based and flat‐dosing regimens and summarized by quartiles of weight. Derived exposure metrics were used in simulations of exposure‐safety (various tumors) and exposure‐efficacy (objective responses; Merkel cell or urothelial carcinoma). Flat dosing was predicted to provide similar exposure to weight‐based dosing, with slightly lower variability. Exposure‐safety and exposure‐efficacy simulations suggested similar benefit:risk profiles for the two dosing regimens. These pharmacometric analyses provided the basis for the US Food and Drug Administration approval of a flat dose of avelumab 800 mg every 2 weeks in approved indications.

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“…In 2010, the FDA approved the anti CTLA4 ipilimumab for melanoma(86). Since 2014, the FDA has approved the anti-PD1 pembrolizumab and nivolumab, and the anti-PD-L1 atezolizumab, avelumab, and durvalumab for several solid tumors (in particular melanoma, lung cancer, urothelial carcinoma, colorectal cancer, hepatic carcinoma, Merkel-cell carcinoma)(94). For hematologic malignancies, nivolumab was approved in 2016 for HL, pembrolizumab in 2017 for HL, and in 2018 for primary mediastinal large B-cell lymphoma(94).…”

Section: Immunotherapeutic Strategies For T Cell Leukemia and Lymphomamentioning

confidence: 99%

Novel Immunotherapies for T Cell Lymphoma and Leukemia

Ghione

Moskowitz

Paola

et al. 2018

Curr Hematol Malig Rep

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Purpose of review: novel immunotherapies such as checkpoint inhibitors, bispecific and chimeric antigen receptor T cells are leading to promising responses when treating solid tumors and hematological malignancies. T cell neoplasms include leukemia and lymphomas that are derived from T cells. These are rare diseases with generally poor clinical outcomes. This review describes the rational and preliminary results of these approaches for people with T cell lymphoma and leukemia. Recent findings: for T cell neoplasms, despite significant research effort, only few agents, such as monoclonal antibodies and allogeneic stem cell transplantation, showed some clinical activity. One of the major hurdles to targeting T cell neoplasms is that activation or elimination of T cells, either normal or neoplastic, can cause significant toxicity. A need to develop novel safe and effective immunotherapies for T cell neoplasms exists. Summary: In this review, we will discuss the rationale for immunotherapy of T cell leukemia and lymphoma and present the most recent therapeutic approaches.

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Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors

Cited by 937 publications

References 99 publications

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma

Novel Immunotherapies for T Cell Lymphoma and Leukemia

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