Dataset Information

Safety and Efficacy of Therapeutic Cancer Vaccines Alone or in Combination With Immune Checkpoint Inhibitors in Cancer Treatment.

ABSTRACT: Therapeutic cancer vaccines have proven to seldom induce dramatic clinical response when used alone, and therefore, they are being studied in combination with additional treatment modalities to achieve optimal treatment activities. Growing preclinical data show that combining vaccines and immune checkpoint inhibitors (ICIs) can prime intensified immunogenicity and modulate immunosuppressive tumor microenvironment. Herein, we focus on the safety and efficacy of approved and promising cancer vaccines alone or combined with ICIs in the treatment of several malignancies. Generally, the majority of clinical trials support the concept of synergy that combination therapy of vaccines and ICIs holds maximized potential to improve clinical outcomes. Importantly, the combination has acceptable safety and minimal additional toxicity compared with single-agent vaccines or ICIs. Additionally, the potential strategies of combining personalized tumor vaccines with ICIs will become priority option and future direction of vaccine development and application and the urgent need to develop effective biomarkers to screen appropriate patient populations and predict response to combination therapy.

SUBMITTER: Zhao J

PROVIDER: S-EPMC6798079 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Safety and Efficacy of Therapeutic Cancer Vaccines Alone or in Combination With Immune Checkpoint Inhibitors in Cancer Treatment.

Zhao Jing J Chen Ye Y Ding Zhen-Yu ZY Liu Ji-Yan JY

Frontiers in pharmacology 20191011

Therapeutic cancer vaccines have proven to seldom induce dramatic clinical response when used alone, and therefore, they are being studied in combination with additional treatment modalities to achieve optimal treatment activities. Growing preclinical data show that combining vaccines and immune checkpoint inhibitors (ICIs) can prime intensified immunogenicity and modulate immunosuppressive tumor microenvironment. Herein, we focus on the safety and efficacy of approved and promising cancer vacci ...[more]

PMID: 31680963

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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

Safety and Efficacy of Therapeutic Cancer Vaccines Alone or in Combination With Immune Checkpoint Inhibitors in Cancer Treatment.

Publications

Safety and Efficacy of Therapeutic Cancer Vaccines Alone or in Combination With Immune Checkpoint Inhibitors in Cancer Treatment.

Similar Datasets

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