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Big opportunities for small molecules in immuno-oncology

Nature Reviews Drug Discovery volume 14, pages 603–622 (2015)Cite this article

Subjects

Key Points

  • The concept of immuno-oncology, using the immune system to fight cancer, dates back 150 years.

  • However, broad clinical success for immunotherapies in cancer has only recently been achieved and comprises a class of biologics that includes vaccines, engineered immune cells and mAbs.

  • Some areas of immune biology cannot be modulated with biologic therapies either due to intracellular access restriction or enzymatic properties that require smaller moieties for intervention.

  • Most small-molecule drugs are tumour-targeted agents, some of which induce immunogenic cell death that could assist an immune response or create synergy in combination with an immunotherapy.

  • Multiple small-molecule drugs aiming to block the function of immune suppressor cells (for example, myeloid-derived suppressor cells, regulatory T cells, dendritic cells and tumour-associated macrophages) have been identified.

  • The hypoxic environment of solid tumours creates a hypoxia–adenosinergic axis of gene regulation, which enforces tumour immune tolerance and can be targeted by small-molecule drugs.

  • Small-molecule immunotherapy for cancer is a growing area ripe with opportunity for exploitation of critical immune biology and potential new drugs to offer patient benefit.

Abstract

The regulatory approval of ipilimumab (Yervoy) in 2011 ushered in a new era of cancer immunotherapies with durable clinical effects. Most of these breakthrough medicines are monoclonal antibodies that block protein–protein interactions between T cell checkpoint receptors and their cognate ligands. In addition, genetically engineered autologous T cell therapies have also recently demonstrated significant clinical responses in haematological cancers. Conspicuously missing from this class of therapies are traditional small-molecule drugs, which have previously served as the backbone of targeted cancer therapies. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. This Review highlights immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms — modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration — are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.

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Figure 1: Immune function and the immune response to cancer.
Figure 2: Small-molecule drug targets to restore cancer immunity in the tumour.
Figure 3: Purinergic and PGE2 signalling in immune cells.

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Acknowledgements

This Review was inspired by the bravery and resolve of cancer patients and their families. The authors also wish to thank R&D leadership as well as immuno-oncology researchers, physicians and administrative staff at GlaxoSmithKline for their continued devotion to cancer medicine innovation, with particular thanks to A. Lockenour for thoughtful discussion and review of the manuscript.

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  1. GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, 19426, Pennsylvania, USA

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

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Correspondence to Axel Hoos.

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J.L.A., J.S., R.S. and A.H. are employees of GlaxoSmithKline. J.L.A., J.S. and R.S. also hold GlaxoSmithKline stocks.

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FURTHER INFORMATION

ClinicalTrials.gov

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Combination Immunotherapy: Small Molecules that Boost Immune Response in Combination with Other Agents (PDF 426 kb)

Supplementary information S2 (table)

Immuno–Modulating SMDs that have Entered Clinical Trials Either as Single–Agent Studies or as Part of a Combination Therapy Exploration. (PDF 741 kb)

Glossary

Dendritic cells

Professional antigen-presenting cells that take up and present antigens. In the tumour microenvironment these cells present antigens from dying tumour cells, which are taken up and processed by immature dendritic cells. Upon cell maturation, and as they migrate to the draining lymph node, they display antigen via HLA class I and II molecules to prime effector T lymphocytes.

Effector T cell

Mediates killing of target cells via cognate antigen recognition on HLA class I molecules.

Regulatory (TReg) cell

CD4+CD25+FOXP3+ cells that are suppressive in nature and dampen CD8+ effector T cell responses.

Natural killer cells

Cells that kill viral and tumour targets via non-MHC restriction.

Tumour-associated macrophages

(TAMs). Arise from anti-inflammatory, pro-tumorigenic M2 macrophages and reside in the tumour stroma, causing inhibition of immune responses, or in blood vessels in the core of the tumour tissue, promoting tumour invasion.

TH1-type response

A CD4+ T cell immune response mediated by pro-inflammatory cytokines (e.g., interferon, interleukin-1 and tumour necrosis factor), which promotes cellular immune responses.

TH2-type response

A CD4+ T cell response driven by interleukin-4, which stimulates antibody production.

Myeloid-derived suppressor cells

(MDSCs). Cells that promote immune suppression of multiple cell types and initiate tumour cell evasion.

Cancer-associated fibroblasts

Components of tumour tissue that support and promote tumour growth and immune cell evasion.

Immunogenic cell death

Cell death that primes an immune response; characterized by release of ATP, high mobility group box 1 (HMGB1) and the pre-apoptotic display of calreticulin.

CD39

Also known as ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase 1), CD39 is a cell surface-bound phosphatase found on lymphocytes and tumours and is responsible for the conversion of extracellular ATP into adenosine.

CD73

Also known as 5′-nucleotidase (5′-NT), CD73 is a cell surface-bound phosphatase found on lymphocytes and tumours and is responsible for the conversion of extracellular ATP into adenosine.

Hypoxia–adenosinergic axis

A programme of gene regulation in response to hypoxia whereby elevated extracellular adenosine mediates a broadly suppressive immune response.

B cells

Lymphocytes that produce antibodies in response to antigen presentation by antigen-presenting cells. B cells may also function as antigen-presenting cells in some instances.

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Adams, J., Smothers, J., Srinivasan, R. et al. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov 14, 603–622 (2015). https://doi.org/10.1038/nrd4596

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