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TNF in the era of immune checkpoint inhibitors: friend or foe?

Abstract

Immune checkpoint inhibitors (ICIs) are effective in the treatment of patients with advanced cancer and have emerged as a pillar of standard cancer care. However, their use is complicated by adverse effects known as immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis. ICI-induced inflammatory arthritis is distinguished from other irAEs by its persistence and requirement for long-term treatment. TNF inhibitors are commonly used to treat inflammatory diseases such as rheumatoid arthritis, spondyloarthropathies and inflammatory bowel disease, and have also been adopted as second-line agents to treat irAEs refractory to glucocorticoid treatment. Experiencing an irAE is associated with a better antitumour response after ICI treatment. However, whether TNF inhibition can be safely used to treat irAEs without promoting cancer progression, either by compromising ICI therapy efficacy or via another route, remains an open question. In this Review, we discuss clinical and preclinical studies that address the relationship between TNF, TNF inhibition and cancer. The bulk of the evidence suggests that at least short courses of TNF inhibitors are safe for the treatment of irAEs in patients with cancer undergoing ICI therapy. Data from preclinical studies hint that TNF inhibition might augment the antitumour effect of ICI therapy while simultaneously ameliorating irAEs.

Key points

  • Different arms of the immune response are important for autoimmune versus anticancer activities, and TNF inhibitors restrain some of these arms while promoting or having a neutral effect on others.

  • Preclinical studies provide evidence that short courses of TNF inhibitors, despite their efficacy in ameliorating immune-related adverse events (irAEs), do not restrain the anticancer effects of immune checkpoint inhibitors (ICIs).

  • TNF inhibitor treatment of rheumatic diseases does not seem to increase the risk of cancer, except for non-melanoma skin cancer and possibly lymphoma.

  • Short courses of TNF inhibitors are likely to be safe in the treatment of ICI-associated irAEs, but data on the safety of long-term TNF inhibitor use for irAEs are lacking.

  • Clinical studies that directly assess the effect of TNF inhibitor treatment on ICI efficacy are required to draw conclusions regarding the safety of TNF inhibitor treatment for irAEs.

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Fig. 1: Pro-tumour and antitumour effects of TNF inhibition and immune checkpoint inhibition.

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Acknowledgements

The work of J.D.W. is funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. J.D.W. is also affiliated with: Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. The authors would like to thank L.B. Ivashkiv at the Hospital for Special Surgery for his comments on the manuscript.

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A.Y.C. and A.R.B. researched data for the article and wrote the article. All authors made substantial contributions to discussions of the content and reviewed/edited the manuscript before submission.

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Correspondence to Anne R. Bass.

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J.D.W. is a consultant for Adaptive Biotech, Amgen, Apricity, Arsenal, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F Star, Imvaq, Kyowa Hakko Kirin, Merck, Neon Therapeutics, Psioxus, Recepta, Sellas, Serametrix, Surface Oncology, Syndax and Syntalogic, Takara Bio, Trieza and Truvax; receives research support from AstraZeneca, Bristol Myers Squibb and Sephora; and has equity in Adaptive Biotechnologies, Apricity, Arsenal, BeiGene, Imvaq, Linnaeus, Tizona Pharmaceuticals. The other authors declare no competing interests.

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Nature Reviews Rheumatology thanks L. Cappelli, M. Suarez-Almazor and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Chen, A.Y., Wolchok, J.D. & Bass, A.R. TNF in the era of immune checkpoint inhibitors: friend or foe?. Nat Rev Rheumatol 17, 213–223 (2021). https://doi.org/10.1038/s41584-021-00584-4

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