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Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations

Nature Reviews Immunology (2023)Cite this article

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Abstract

The approval of the first immune checkpoint inhibitors provided a paradigm shift for the treatment of malignancies across a broad range of indications. Whereas initially, single-agent immune checkpoint inhibition was used, increasing numbers of patients are now treated with combination immune checkpoint blockade, where non-redundant mechanisms of action of the individual agents generally lead to higher response rates. Furthermore, immune checkpoint therapy has been combined with various other therapeutic modalities, including chemotherapy, radiotherapy and other immunotherapeutics such as vaccines, adoptive cellular therapies, cytokines and others, in an effort to maximize clinical efficacy. Currently, a large number of clinical trials test combination therapies with an immune checkpoint inhibitor as a backbone. However, proceeding without inclusion of broad, if initially exploratory, biomarker investigations may ultimately slow progress, as so far, few combinations have yielded clinical successes based on clinical data alone. Here, we present the rationale for combination therapies and discuss clinical data from clinical trials across the immuno-oncology spectrum. Moreover, we discuss the evolution of biomarker approaches and highlight the potential new directions that comprehensive biomarker studies can yield.

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Fig. 1: Roadmap to rational combinations.

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Acknowledgements

This work was supported by the Parker Institute for Cancer Immunotherapy (L.H.B.). This work was supported by the University of Pittsburgh UPMC Hillman Cancer Center Award P30CA04904 (Y.G.N.). The authors thank D. Gilmartin for assistance with the references in this paper.

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  1. University of California San Francisco, Microbiology and Immunology, San Francisco, CA, USA

    Lisa H. Butterfield

  2. UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Yana G. Najjar

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The authors contributed equally to all aspects of the article.

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Correspondence to Lisa H. Butterfield or Yana G. Najjar.

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L.H.B. declares the following unrelated advisory activities: Calidi Scientific and Medical Advisory Board, 6 April 2017–2023; KaliVir, Scientific Advisory Board, 2018–2023; Torque Therapeutics, Scientific Advisory Board, 2018–2020; Khloris, Scientific Advisory Board, 2019–2023; Pyxis, Scientific Advisory Board, 2019–2023; CytomX, Scientific Advisory Board, 2019–2023; DCprime, Scientific Advisory Board meeting, November 2020; RAPT, Scientific Advisory Board, 2020–2023; Takeda, scientific advisor, 2020–2023; EnaraBio scientific adviser, February 2021; Federation Bio, scientific adviser, 2022; and Pfizer, scientific adviser, 2022. Current contact: lisa.butterfield@merck.com. Y.G.N. declares the following unrelated advisory activities: Scientific Advisory Board/consulting: Merck, InterVenn Bio, Novartis, BMS, Pfizer and Immunocore. Non-continuing education honoraria: Immunocore. Travel cost/accommodations: Istari Oncology. Research funding (to institution): Merck, Pfizer, BMS and Replimune.

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Glossary

Abscopal effect

The observation that a local treatment delivered to one anatomical site (for example, the tumour) leads to an effect at a distant anatomical site (for example, a metastatic tumour deposit), suggesting circulating systemic immunity.

Antigenic breadth

The number of different tumour antigens (or epitopes therein) that the immune system reacts to.

Epitope spreading

The phenomenon identified in autoimmunity in which an immune response to one tissue antigen leads to cell death, additional antigen release in inflammatory conditions and subsequent rounds of immune response to new antigens.

Hypothesis-generating biomarkers

Broad testing of immune response that is not directed towards a specific scientific hypothesis, but which instead is designed to provide data to be mined to identify unanticipated hypotheses.

Immune monitoring of patients

Immune response testing performed in clinical trials on patient blood and other tissue samples to determine the effects of a therapy.

ImmunoPET

PET using labels that detect immune cells (for example, CD8+ T cells).

Immunophenotype

The observable characteristics that relate to the immune system and immune reactivity.

M1-polarized

Myeloid cells (macrophages) whose functions are aligned with antitumour functions, so called in reference to the ‘type 1’ T cell paradigm.

M2-polarized

Myeloid cells (macrophages) whose functions are in opposition to antitumour functions, so called in reference to the ‘type 2’ T cell paradigm.

Tertiary lymphoid structures

Organized immune structures that can be detected in different diseased tissues that resemble a secondary lymphoid structure containing T and B cells, antibodies and antigen-presenting cells.

T cell engagers

Chimeric molecules, commonly with antibody structures, which simultaneously bind to the CD3 molecule on the T cell surface and a cell-surface tumour protein to connect T cells with tumour cells directly.

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Butterfield, L.H., Najjar, Y.G. Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00973-8

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  • DOI: https://doi.org/10.1038/s41577-023-00973-8

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