Acquired Resistance to Immune Checkpoint Inhibitors

Schoenfeld, Adam J.; Hellmann, Matthew D.

doi:10.1016/j.ccell.2020.03.017

Cited by 531 publications

(478 citation statements)

References 114 publications

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“…B2M is mutated or deleted in about 5% of lung cancers) [ 21 ] and also other pathway members are inactivated [ 22 ]. Importantly, IO may increase the frequency of such mutations [ 19 , 23 , 24 ] suggesting an active immune-editing of cells failing to present neo-epitopes.…”

Section: Immunopathology Of Nsclc and Evolution Of Io Resistancementioning

confidence: 99%

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

et al. 2020

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Immunotherapy (IO) has revolutionized the therapy landscape of non-small cell lung cancer (NSCLC), significantly prolonging the overall survival (OS) of advanced stage patients. Over the recent years IO therapy has been broadly integrated into the first-line setting of non-oncogene driven NSCLC, either in combination with chemotherapy, or in selected patients with PD-L1high expression as monotherapy. Still, a significant proportion of patients suffer from disease progression. A better understanding of resistance mechanisms depicts a central goal to avoid or overcome IO resistance and to improve patient outcome. We here review major cellular and molecular pathways within the tumor microenvironment (TME) that may impact the evolution of IO resistance. We summarize upcoming treatment options after IO resistance including novel IO targets (e.g. RIG-I, STING) as well as interesting combinational approaches such as IO combined with anti-angiogenic agents or metabolic targets (e.g. IDO-1, adenosine signaling, arginase). By discussing the fundamental mode of action of IO within the TME, we aim to understand and manage IO resistance and to seed new ideas for effective therapeutic IO concepts.

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Section: Immunopathology Of Nsclc and Evolution Of Io Resistancementioning

confidence: 99%

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

et al. 2020

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“…Although ICI demonstrated good clinical activity, data from human studies indicated that only a fraction of patients could really benefit of this type of therapy, that, unfortunately, in the majority of cases resulted largely ineffective or, as described above, even detrimental [ 134 ]. The current view is that tumors that are characterized by an inflamed/immunogenic phenotype, the so-called “hot” tumors, have the highest chance to properly respond to ICI.…”

Section: Possible Tumor-related Mechanisms Of Hpdmentioning

confidence: 99%

Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know

Camelliti

Noci

Bianchi

et al. 2020

J Exp Clin Cancer Res

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Immune checkpoint inhibitors (ICIs) have made a breakthrough in the treatment of different types of tumors, leading to improvement in survival, even in patients with advanced cancers. Despite the good clinical results, a certain percentage of patients do not respond to this kind of immunotherapy. In addition, in a fraction of nonresponder patients, which can vary from 4 to 29% according to different studies, a paradoxical boost in tumor growth after ICI administration was observed: a completely unpredictable novel pattern of cancer progression defined as hyperprogressive disease. Since this clinical phenomenon has only been recently described, a universally accepted clinical definition is lacking, and major efforts have been made to uncover the biological bases underlying hyperprogressive disease. The lines of research pursued so far have focused their attention on the study of the immune tumor microenvironment or on the analysis of intrinsic genomic characteristics of cancer cells producing data that allowed us to formulate several hypotheses to explain this detrimental effect related to ICI therapy. The aim of this review is to summarize the most important works that, to date, provide important insights that are useful in understanding the mechanistic causes of hyperprogressive disease.

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“…Despite the great success of cancer immunotherapy using ICIs, their therapeutic bene ts are limited by either various resistance mechanisms [54] or irAEs [3]. Gut microbiome, due to its proven role in cancer development and immune regulation, has gained increasing expectation as a potential armamentarium to further improve cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review

Huang

Liu

et al. 2020

Preprint

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Background: Gut microbiome is proved to affect the activity of immunotherapy in certain tumors. However, little is known if there is universal impact on both the treatment response and adverse effects (AEs) of immune checkpoint inhibitors (ICIs) across multiple solid tumors, and whether such impact can be modulated by common gut microbiome modifiers, such as antibiotics and diet.Methods: A systematic search in PubMed followed by stringent manual review were performed to identify clinical cohort studies that evaluated the relevance of gut microbiome to ICIs (response and/or AEs, 12 studies), or association of antibiotics with ICIs (17 studies), or impact of diet on gut microbiome (16 studies). Only original studies published in English before April 1st, 2020 were used. Qualified studies identified in the reference were also included.Results: At the phylum level, patients who had enriched abundance in Firmicutes and Verrucomicrobia almost universally had better response from ICIs, whereas those who were enriched in Proteobacteria universally presented with unfavorable outcome. Mixed correlations were observed for Bacteroidetes in relating to treatment response. Regarding the AEs, Firmicutes correlated to higher incidence whereas Bacteroidetes were clearly associated with less occurrence. Interestingly, across various solid tumors, majority of the studies suggested a negative association of antibiotic use with clinical response from ICIs, especially within 1-2 month prior to the initiation of ICIs. Finally, we observed a significant correlation of plant-based diet in relating to the enrichment of “ICI-favoring” gut microbiome (P = 0.0476).Conclusions: Gut microbiome may serve as a novel modifiable biomarker for both the treatment response and AEs of ICIs across various solid tumors. Further study is needed to understand the underlying mechanism, minimize the negative impact of antibiotics on ICIs, and gain insight regarding the role of diet so that this important lifestyle factor can be harnessed to improve the therapeutic outcomes of cancer immunotherapy partly through its impact on gut microbiome.

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Acquired Resistance to Immune Checkpoint Inhibitors

Cited by 531 publications

References 114 publications

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook

Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know

Relating Gut Microbiome and Its Modulating Factors to Immunotherapy in Solid Tumors: A Systematic Review

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