Big opportunities for small molecules in immuno-oncology

Adams, Jerry L.; Smothers, James; Srinivasan, Roopa; Hoos, Axel

doi:10.1038/nrd4596

Cited by 387 publications

(317 citation statements)

References 163 publications

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“…A growing body of evidence suggests that cancer initiation and progression depends on the ability of cancer cells to evade host immunosurveillance (21,22 (26). Therapeutic strategies targeting these cell populations are emerging (27)(28)(29)(30)(31) and may benefit patients in the future. However, prior to the therapeutic exploitation of these cell populations, it is important to evaluate their role and interactions in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

et al. 2016

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Abstract.Immunotherapy is a promising therapeutic option for patients with non-small cell lung cancer (NSCLC) who do not qualify for surgery. In patients with advanced NSCLC, systemic immune suppression is frequently observed, therefore, researchers are investigating the tumor microenvironment for less invasive and more effective methods of treating lung cancer. Monocytic myeloid-derived suppressor cells (Mo-MDSCs) are potent suppressors of tumor immunity; therefore, this population may significantly impede the application of immunotherapy to treat cancer. The present study evaluated the distribution of Mo-MDSCs and monocytes/macrophages in the peripheral blood, lymph nodes and tumor tissue of patients with NSCLC. Furthermore, the profiles of cytokines produced by these cell populations, including interleukin (IL)-1β, IL-12/23p40, IL-10, transforming growth factor-β (TGF-β) and tumor necrosis factor (TNF), were compared. The cell populations and the expression of cytokines were assessed by flow cytometry after 4 h in culture with mitogens and Brefeldin A. Mo-MDSCs were more numerous than monocytes/macrophages in all tissues and their prevalence was highest in the peripheral blood; they expressed higher levels of TGF-β than monocytes/macrophages in all

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Section: Discussionmentioning

confidence: 99%

Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

et al. 2016

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“…1 The complexity of the immune system and immune response provides enormous scope for different immuno-oncology agents and strategies. 3 The immuno-oncology agents approved so far show that this treatment modality offers distinct and, in many cases, improved activity over traditional chemotherapy and targeted therapeutic methods. This approach also provides the potential for further improvement as strategies for the use of immunotherapeutic drugs are refined.…”

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confidence: 99%

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Sheng

Srivastava

Sanghavi

et al. 2017

The Journal of Clinical Pharma

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Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches. Keywords immunopharmacology, oncology, clinical pharmacology, clinical trials, pharmacology, immunotherapy, checkpoint inhibitorsIt could be said that if there were a book chronicling the history and progression of cancer treatment, we are now moving on from the chapter describing the time of sole reliance on chemotherapy, the chapter outlining the advent of targeted therapy is partially completed, and a new chapter on immuno-oncology is just beginning. The past few years have seen the regulatory approval of several immuno-oncology agents (Figure 1), including 6 immune checkpoint inhibitors: ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), atezolizumab (Tecentriq; Genentech), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca). 1,2Immunotherapy in oncology is a switch from the cell-killing modality using relatively nonspecific cytotoxic methods (chemotherapy) or therapies that target cancer-specific pathways to methods that employ the patients' immune system to attack cancer. The immuno-oncology approach calls on the understanding of complex signaling processes of effector and regulatory...

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“…Considering the efect of tumor-derived immunosuppressive molecules on the decrease in the expression of activating NK cell receptors, early stage clinical trials have been introduced that use monoclonal antibodies, alone or in combination, to neutralize TGF-β, IDO, or PD-1 checkpoint inhibitor in diferent malignancies that led to improved antitumor NK cell function [77].…”

Section: Tumor-induced Immunosuppressionmentioning

confidence: 99%

The Role of Activating and Inhibitory NK Cell Receptors in Antitumor Immune Response

Konjević¹,

Vuletić²,

Martinović³

et al. 2017

Natural Killer Cells

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Natural killer (NK) cells express many newly identiied activating and inhibitory receptors that upon engagement by cognate ligands on target tumor cells regulate NK cell antitumor activity. Recently, several paired NK cell receptor families that include receptors with similar binding speciicities but opposite function have been deined. The expression of most important activating receptors, natural killer group 2D (NKG2D), natural cytotoxic receptors (NCR), DNAX accessory molecule-1 (DNAM1) and activating killer cell immunoglobulin-like receptors (KAR) is often decreased, while the expression of most prominent inhibitory NK cell receptors, killer cell inhibitory immunoglobulin-like receptors (KIR) and CD94/NKG2A, may occasionally be increased in malignancies. These data indicate that impaired NK cell antitumor response results from NK cell receptor alterations induced by suppressive factors in the tumor microenvironment, including cytokines, growth factors, enzymes and metabolites, as well as by chronic NK cell receptor engagement by the tumor. The established alterations in NK cell receptor expression in cancer patients represent potential disease biomarkers and may aid in choosing therapies that upregulate activating or block inhibitory receptor function. Accumulating knowledge of NK cell biology has been helpful in creating novel therapeutic approaches that by release from tumor-inluenced immunosuppression potentiate NK cell activity in cancer patients.

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Big opportunities for small molecules in immuno-oncology

Cited by 387 publications

References 163 publications

Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

The Role of Activating and Inhibitory NK Cell Receptors in Antitumor Immune Response

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