Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists

Zhang, Jinfeng; Yan, Wanfeng; Duan, Wenwen; Wüthrich, Kurt; Cheng, Jianjun

doi:10.3390/ph13090237

Cited by 24 publications

(23 citation statements)

References 70 publications

(116 reference statements)

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“…To this end, ongoing clinical trials testing the antitumor activity and safety of Etrumadenant will begin reveal the potential of A 2A/B AR dual antagonism. 188 However, it is important to note that adenosine signaling through A 2A AR and A 2B AR is important for normal physiological functions such as maintenance of the sleep cycle and cardiovascular regulation, so non-tissue-specific blockade of adenosine signaling could have safety concerns. 189 190 Alternatively, it may be possible to degrade the adenosine molecule itself using an enzymatic therapy, similar to the PEG-KYNase mechanism of action.…”

Section: Challenges and Pathways Forwardmentioning

confidence: 99%

Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward

Jennings

Munn

Blazeck

2021

J Immunother Cancer

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Tumors accumulate metabolites that deactivate infiltrating immune cells and polarize them toward anti-inflammatory phenotypes. We provide a comprehensive review of the complex networks orchestrated by several of the most potent immunosuppressive metabolites, highlighting the impact of adenosine, kynurenines, prostaglandin E2, and norepinephrine and epinephrine, while discussing completed and ongoing clinical efforts to curtail their impact. Retrospective analyses of clinical data have elucidated that their activity is negatively associated with prognosis in diverse cancer indications, though there is a current paucity of approved therapies that disrupt their synthesis or downstream signaling axes. We hypothesize that prior lukewarm results may be attributed to redundancies in each metabolites’ synthesis or signaling pathway and highlight routes for how therapeutic development and patient stratification might proceed in the future.

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Section: Challenges and Pathways Forwardmentioning

confidence: 99%

Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward

Jennings

Munn

Blazeck

2021

J Immunother Cancer

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“…Adenosine and ATP are present at exceptionally low concentrations in extracellular fluids. However, inflammation, ischemia, or the cancer process can lead to the release of ATP through transport channels in cell membranes, active exocytosis, and directly from damaged cells [ 89 , 90 , 91 ]. Extracellular ATP acts as a danger-associated molecular pattern (DAMP) to promote the immune response.…”

Section: Use Of Non-specific Immune System Stimulation and Tumour Microenvironment Modification In Immune Combination Therapiesmentioning

confidence: 99%

“…Under the influence of this stimulation, the expression of immune checkpoints including PD-1, CTLA-4, and LAG-3 increases on effector lymphocytes. Therefore, it is not surprising that molecules that block adenosine binding to the A2a receptor and molecules that inhibit the activity of the CD39 and CD73 enzymes have been developed and used in combination with anti-PD-1 or anti-CTLA-4 antibodies in early phase clinical trials in cancer patients [ 89 , 90 , 91 ].…”

Section: Use Of Non-specific Immune System Stimulation and Tumour Microenvironment Modification In Immune Combination Therapiesmentioning

confidence: 99%

Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

Wojas‐Krawczyk

Krawczyk

Gil

et al. 2021

Cancers

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Due to the limited effectiveness of immunotherapy used as first-line monotherapy in patients with non-small-cell lung cancer (NSCLC), the concepts of combining classical immunotherapy based on immune checkpoint antibodies with other treatment methods have been developed. Pembrolizumab and atezolizumab were registered in combination with chemotherapy for the treatment of metastatic NSCLC, while durvalumab found its application in consolidation therapy after successful chemoradiotherapy in patients with locally advanced NSCLC. Exceptionally attractive, due to their relatively low toxicity and high effectiveness, are treatment approaches in which a combination of two different immunotherapy methods is applied. This method is based on observations from clinical trials in which nivolumab and ipilimumab were used as first-line therapy for advanced NSCLC. It turned out that the dual blockade of immune checkpoints activated T lymphocytes in different compartments of the immune response, at the same time affecting the downregulation of immune suppressor cells (regulatory T cells). These experiments not only resulted in the registration of combination therapy with nivolumab and ipilimumab, but also initiated other clinical trials using immune checkpoint inhibitors (ICIs) in combination with other ICIs or activators of costimulatory molecules found on immune cells. There are also studies in which ICIs are associated with molecules that modify the tumour environment. This paper describes the mechanism of the synergistic effect of a combination of different immunotherapy methods in NSCLC patients.

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“…In addition, the A2A adenosine receptor is an important negative regulator of immune cells in protecting normal tissues from inflammatory damage [26] . Again, there are several pharmacological strategies using selective antagonists to block this pathway and thereby increase anti-tumor immunity [27] . However, at present, monoclonal antibodies, so-called immune checkpoint inhibitors, which block PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab, or atezolizumab) are increasingly used to "release the brake" of the immune system and thus to increase the activity of the immune system against the tumor.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immuno-oncology in triple-negative breast cancer

Heimes¹,

Schmidt²

2021

JCMT

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The immune system plays an important role in breast cancer. Triple-negative breast cancer (TNBC) has a higher mutational load compared to other subtypes. In addition, higher levels of tumor-associated antigens suggests that immunotherapies are a promising treatment option especially for TNBC. Our review discusses both the complexity of the immune system and the cancer immune-cell cycle. In fact, a higher level of tumor-infiltrating lymphocytes is associated with an improved prognosis as well as a better response to chemotherapy in TNBC. Important target structures within the cancer immune-cell cycle are the so-called "immune checkpoints". Immune checkpoint inhibitors (ICPi) block the interaction of certain cell surface proteins that serve as "brakes" of immune reactions. Recent studies have shown ICPi improved survival in early as well as advanced TNBC. However, this has the price of increasing, mainly, immune-mediated toxicity. ICPi strengthen tumor-specific T cell-mediated immunity by "releasing the brake" of the immune system. In combination with chemotherapy, ICPi are already approved for TNBC. As a further step, individualized vaccination strategies against tumor-associated neoantigens represent another promising approach. A liposome-formulated intravenous RNA vaccine encoding different tumorassociated antigens is currently being studied in TNBC and leads to neoantigen-specific immune responses. These novel strategies will improve the prognosis of patients with triple-negative breast cancer.

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Tumor Immunotherapy Using A2A Adenosine Receptor Antagonists

Cited by 24 publications

References 70 publications

Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward

Immunosuppressive metabolites in tumoral immune evasion: redundancies, clinical efforts, and pathways forward

Two Complementarity Immunotherapeutics in Non-Small-Cell Lung Cancer Patients—Mechanism of Action and Future Concepts

Immuno-oncology in triple-negative breast cancer

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