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Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors

Abstract

Conventional chemotherapeutics have been developed into clinically useful agents based on their ability to preferentially kill malignant cells, generally owing to their elevated proliferation rate. Nonetheless, the clinical activity of various chemotherapies is now known to involve the stimulation of anticancer immunity either by initiating the release of immunostimulatory molecules from dying cancer cells or by mediating off-target effects on immune cell populations. Understanding the precise immunological mechanisms that underlie the efficacy of chemotherapy has the potential not only to enable the identification of superior biomarkers of response but also to accelerate the development of synergistic combination regimens that enhance the clinical effectiveness of immune checkpoint inhibitors (ICIs) relative to their effectiveness as monotherapies. Indeed, accumulating evidence supports the clinical value of combining appropriately dosed chemotherapies with ICIs. In this Review, we discuss preclinical and clinical data on the immunostimulatory effects of conventional chemotherapeutics in the context of ICI-based immunotherapy.

Key points

  • The therapeutic efficacy of conventional chemotherapeutic agents involves a considerable immunological component.

  • Conventional chemotherapy can mediate immunostimulatory effects by targeting cancer cells or immune cells as well as by altering whole-body physiology.

  • A range of parameters reflecting the immunological competence of the tumour microenvironment of the patient can influence the efficacy of chemotherapy.

  • Immunostimulatory chemotherapeutics stand out as promising partners for combination regimens involving immune checkpoint inhibitors, although additional research is required to identify the optimal regimens.

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Fig. 1: Principles of immunomodulation by conventional chemotherapeutics.
Fig. 2: Immunogenic cell death prediction scores for chemotherapies with confirmed or potential immunogenic effects.
Fig. 3: Immunological parameters affecting chemotherapy responses in patients with cancer.
Fig. 4: Overview of ongoing clinical trials involving one or more immunogenic cell death inducers in combination with immune checkpoint inhibitors in patients with cancer.

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Acknowledgements

We thank Alain Sauvat (Gustave Roussy Institute, Villejuif, France) for computing the ICD score in Fig. 2. LG is supported by a Breakthrough Level 2 grant from the US Department of Defense, Breast Cancer Research Program (#BC180476P1), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer, by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society, by a startup grant from the Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US), by a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, US), and by donations from Phosplatin, the Luke Heller TECPR2 Foundation (Boston, US) and Sotio a.s. (Prague, Czech Republic). GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale; a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Institut National du Cancer; Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).

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L.G., J.H., A.B. and G.K. researched data for this article. L.G., L.Z. and G.K. made a substantial contribution to discussions of content. LG and GK wrote the manuscript. All authors edited, reviewed and approved the manuscript prior to submission.

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Correspondence to Lorenzo Galluzzi or Guido Kroemer.

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Competing interests

L.G. declares consultancy fees from Astra Zeneca, Inzen, the Luke Heller TECPR2 Foundation, and OmniSEQ and is a member of the Scientific Advisory Committee of Boehringer Ingelheim, The Longevity Labs and OmniSEQ. L.Z. is a scientific co-founder of everImmune. G.K. has conducted contract research for Bayer Healthcare, Genentech, Glaxo Smyth Kline, Institut Mérieux, Kaleido, Lytix Pharma, Nucana, Oncolinx, PharmaMar, Samsara, Sotio and Vasculox, is on the Board of Directors of the Bristol Myers Squibb Foundation France, and is a scientific co-founder of everImmune, Samsara Therapeutics and Therafast Bio. J.H. and A.B. declare no competing interests.

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Galluzzi, L., Humeau, J., Buqué, A. et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol 17, 725–741 (2020). https://doi.org/10.1038/s41571-020-0413-z

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