Tumor and Systemic Immunomodulatory Effects of MEK Inhibition

Dennison, Lauren; Mohan, Aditya; Yarchoan, Mark

doi:10.1007/s11912-020-01008-4

Cited by 7 publications

(21 citation statements)

References 72 publications

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“…Our data provide initial evidence that MEK inhibitors are immunomodulatory in BTC and augment antitumor T cell immunity and/or inhibit immunosuppressive axes within the tumor microenvironment. The observation of enhanced expression of multiple genes involved antigen-processing and presentation in the present study is also consistent with preclinical studies (26,34). We also observed that patients with higher baseline expression or smaller fold changes in the expression of multiple inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.…”

Section: Discussionsupporting

confidence: 91%

“…As compared with atezolizumab monotherapy, there was a trend toward higher expression of antigen-processing and presentation genes, including TAP-associated glycoprotein (TAPBP), immunoproteasome expression (proteasome subunit beta type-8, PSMB8), and human leukocyte antigen (HLA) in the combination arm, as well as enhanced expression of interferon signaling pathway member interferon-induced transmembrane protein 2 (IFITM2). While these differences are exploratory in nature, they support the idea that cobimetinib may invigorate antitumor immunity in the TME and are in broad agreement with preclinical models of MEK inhibition (26,34).…”

Section: Resultssupporting

confidence: 62%

“…We also observed that patients with higher baseline expression or smaller fold changes in the expression of multiple inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination. This work is hypothesis generating, but suggests the possibility that the reversal or prevention of T cell exhaustion is a key mechanism of systemic MEK inhibition immunomodulation, as previously shown in preclinical models (26,34). Overall, these clinical trial biomarkers suggest that MEK inhibitor therapy modulated the response to anti-PD-L1 immunotherapy and was of benefit for some patients.…”

Section: Discussionsupporting

confidence: 57%

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Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

Yarchoan¹,

Cope²,

Ruggieri³

et al. 2021

Journal of Clinical Investigation

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BACKGROUND. MEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition. METHODS.This open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS). RESULTS.Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35-0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination. CONCLUSION.The combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs. TRIAL REGISTRATION. ClinicalTrials.gov NCT03201458.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 62%

Section: Discussionsupporting

confidence: 57%

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Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

Yarchoan¹,

Cope²,

Ruggieri³

et al. 2021

Journal of Clinical Investigation

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“…As a result, RAS is locked in GTP-bound state, leading to the hyperactive downstream pathways and tumor growth [209,210]. Recent studies have shown that RAS and its downstream pathways participated in cancer immune escape: negatively regulating MHC-I expression on cancer cells, increasing the cell-intrinsic PD-L1 level, elevating immune suppression-associated cytokine production [211,212]. RAS-targeted therapy abrogated RAS-MAPK/PI3K-AKT-involved immune evasion, synergizing with α-PD-1/PD-L1 [213,214].…”

Section: Ras-targeted Therapy Plus α-Pd-1/pd-l1mentioning

confidence: 99%

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

et al. 2022

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Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.

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“…Among these pathways, the B cell receptor pathway is known to influence the B cell signalling network and stimulate autoimmune disease pathogenesis, resulting in IMN (Motavalli et al, 2019). The MAPK signalling pathway also plays a significant role in the immunomodulatory effects of T cells and B cells (Dennison, Mohan & Yarchoan, 2021). The results of functional annotation analysis suggest that immune-related genes warrant future investigation.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of miRNA–mRNA network in idiopathic membranous nephropathy by bioinformatics analysis

Zhang

Yuan

et al. 2021

PeerJ

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Background Currently, several specific antigens, M-type receptor for secretory phospholipase A2(PLA2R1), thrombospondin type-1 domain-containing 7A(THSD7A), and neural epidermal growth factor-like 1 protein (NELL-1), are discovered associated with the onset of idiopathic membranous nephropathy (IMN). But the pathomechanisms of IMN still need to be further claried. Understanding the mechanisms of IMN is required to improve its diagnosis and treatment. Methods In this study, we constructed miRNA regulatory networks to investigate IMN development. Moreover, miRNAs and mRNAs that were differentially expressed between Idiopathic Membranous Nephropathy (IMN) patients and normal controls were examined using the GSE115857 dataset and our previous sequence study. DE miRNA target genes were determined based on the FUNRICH software, starBase, miRDB, and miRWalk, and an miRNA-mRNA network was designed using DE-mRNAs that were negatively correlated with DE-miRNAs. The miRNA-mRNA network contained 228 miRNA-mRNA pairs. Thereafter, we conducted KEGG pathway, GO functional annotation, immune-related gene screening, protein interaction networks, and potential hub gene analyses. Furthermore, 10 miRNAs and 10 genes were determined and preliminarily validated using the validation dataset from GEO. Finally, we identified which pair may offer more accurate diagnosis and therapeutic targets for IMN. Results Two miRNA-mRNA pairs, miR-155-5p-FOS and miR-146a-5p-BTG2, were differentially expressed in IMN, indicating that these genes may affect IMN through immune processes. These findings may offer more accurate diagnoses and therapeutic targets for IMN.

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Tumor and Systemic Immunomodulatory Effects of MEK Inhibition

Cited by 7 publications

References 72 publications

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions

Integrative analysis of miRNA–mRNA network in idiopathic membranous nephropathy by bioinformatics analysis

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