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  • Review Article
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The expanding role for small molecules in immuno-oncology

Nature Reviews Drug Discovery volume 21, pages 821–840 (2022)Cite this article

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Abstract

The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, there is an increasing interest in small-molecule immuno-oncology drugs that address intracellular pathways, some of which have recently entered clinical trials. In parallel, small molecules that target pro-tumorigenic pathways in cancer cells and the tumour microenvironment have been found to have immunostimulatory effects that synergize with the action of ICI antibodies, leading to the approval of an increasing number of regimens that combine such drugs. Combinations with small molecules targeting cancer metabolism, cytokine/chemokine and innate immune pathways, and T cell checkpoints are now under investigation. This Review discusses the recent milestones and hurdles encountered in this area of drug development, as well as our views on the best path forward.

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Fig. 1: Modulation of T cell activity through immunogenic tumour cell death.
Fig. 2: Structurally diverse examples of CSF1R inhibitors.
Fig. 3: Metabolic pathway inhibitors.
Fig. 4: The interplay of the adenosine signalling and STING pathways.
Fig. 5: Tumour progression and subversion of antitumour immunity mediated by the kynurenine pathway.
Fig. 6: Compounds that target innate immune pathways.
Fig. 7: Intracellular targets involved in immune receptor signalling.
Fig. 8: Examples of small-molecule checkpoint inhibitors.
Fig. 9: Examples of small molecules targeting mediators of immune receptor signaling in T-cells.
Fig. 10: Overview of immunoregulatory hurdles imposed by the tumour microenvironment and small-molecule targets through which these may be overcome.

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Acknowledgements

R.O. receives funding from the K. H. Bauerstiftung. The authors gratefully acknowledge A. Unzue-Lopez, Merck Healthcare KGaA, Darmstadt, Germany, who helped to proofread the manuscript and to kindly double-check the accuracy of chemical structures in this article. The authors also gratefully acknowledge T. Johnson, EMD Serono, Billerica, MA, USA, who created the picture of the co-crystal structure of compound 24 in HPK1 from the Protein Data Bank.

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Authors and Affiliations

  1. Department of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany

    Rienk Offringa

  2. DKFZ–Bayer Immunotherapeutics Laboratory, German Cancer Research Center, Heidelberg, Germany

    Rienk Offringa

  3. Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany

    Rienk Offringa

  4. Merck Healthcare KGaA, Healthcare R&D, Discovery and Development Technologies, Darmstadt, Germany

    Lisa Kötzner

  5. EMD Serono, Healthcare R&D, Discovery and Development Technologies, Billerica, MA, USA

    Bayard Huck & Klaus Urbahns

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The authors contributed equally to all aspects of the article.

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Correspondence to Rienk Offringa or Klaus Urbahns.

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R.O. is a recipient of research funding through the DKFZ–Bayer strategic research alliance. L.K., K.U. are employees of Merck Healthcare KGaA and B.H. is an employee at EMD Serono, respectively, and declare no competing interests.

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Glossary

Immune checkpoint inhibitor

(ICI). A compound, often an antibody, that blocks the functionality of immune checkpoint proteins.

Ipilimumab

Anti-cytotoxic lymphocytic protein 4 (CTLA4) antibody, marketed under the brand name Yervoy, developed by Bristol-Myers Squibb, that obtained its first FDA approval in March 2011.

Pembrolizumab

Anti-PD1 antibody, marketed under the name Keytruda, developed by Merck & Co., that obtained its first FDA approval in September 2014.

Nivolumab

Anti-PD1 antibody, marketed under the name Opdivo, developed by Bristol-Myers Squibb, that obtained its first FDA approval in December 2014.

Tumour microenvironment

(TME). The environment around a tumour, including the surrounding blood vessels, immune cells, fibroblasts, signalling molecules and the extracellular matrix.

Immunogenic cell death

(ICD). Cell death resulting from the disruption of cell integrity and/or stress factors, including cytostatic drugs, that cause the release of intracellular components into the extracellular environment and pro-inflammatory signals that initiate an immune response. These downstream events are avoided in the context of apoptotic cell death.

Myeloid-derived suppressor cells

(MDSCs). A diverse population of immature myeloid cells with potent immunosuppressive activity that is often enriched in the tumour microenvironment.

Atezolizumab

Anti-PDL1 antibody, marketed under the name Tecentriq, developed by Genentech/Roche that obtained its first FDA approval in May 2016.

Spartalizumab

Anti-PD1 antibody developed by Novartis that is under investigation in multiple clinical trials.

Avelumab

Anti-PDL1 antibody, marketed under the name Bavencio, developed by Merck KGaA and Pfizer that obtained its first FDA approval in March 2017.

Zimberelimab

Anti-PD1 antibody developed by Arcus Biosciences that is under investigation in multiple clinical trials.

FOLFOX

A chemotherapy regimen consisting of folinic acid, 5-fluorouracil, irinotecan and oxaliplatin.

Anergy

A tolerance mechanism in which the lymphocyte is functionally inactivated but remains alive in a hyporesponsive state.

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Offringa, R., Kötzner, L., Huck, B. et al. The expanding role for small molecules in immuno-oncology. Nat Rev Drug Discov 21, 821–840 (2022). https://doi.org/10.1038/s41573-022-00538-9

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