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Combination approaches in NSCLC involving immune checkpoint inhibitors.

ABSTRACT: Immune checkpoint inhibition has been proven to be highly efficacious in NSCLC and associated with durable responses in a limited number of patients. Chemotherapy and targeted therapies, which have also expanded rapidly in this field lead to high response rates and improved survival although inevitably resistance occurs and hence treatment failure. There is increasing evidence showing that chemotherapy and targeted therapy interplay with the immune system including exerting effects on tumor cells and the host immune cells. Naturally combining both of these treatment modalities to induce cytotoxic effects on tumor cells to release tumor antigens and priming of the immune system should in turn lead to enhanced anticancer activity. This review will explore some of the preclinical rationale and clinical trial data we have to date on combining various systemic therapies with immunotherapies.

SUBMITTER: Arulananda S

PROVIDER: S-EPMC6310331 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Combination approaches in NSCLC involving immune checkpoint inhibitors.

Arulananda Surein S Rivalland Gareth G John Thomas T

Lung cancer management 20161103 4

Immune checkpoint inhibition has been proven to be highly efficacious in NSCLC and associated with durable responses in a limited number of patients. Chemotherapy and targeted therapies, which have also expanded rapidly in this field lead to high response rates and improved survival although inevitably resistance occurs and hence treatment failure. There is increasing evidence showing that chemotherapy and targeted therapy interplay with the immune system including exerting effects on tumor cell ...[more]

PMID: 30643561

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Project description:Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of immune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been effective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are unresponsive to current endocrine therapies.

Dataset Information

Combination approaches in NSCLC involving immune checkpoint inhibitors.

Publications

Combination approaches in NSCLC involving immune checkpoint inhibitors.

Similar Datasets

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