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Turning up the heat: CTLA4 blockade in urothelial cancer

Nature Reviews Urology volume 21, pages 22–34 (2024)Cite this article

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Abstract

Anti-PD1 and anti-PDL1 monotherapies have shown clinical efficacy in stage IV urothelial cancer and are integrated into current clinical practice. However, only a small number of the patients treated with single-agent checkpoint blockade experience an antitumour response. Insufficient priming or inhibitory factors in the tumour immune microenvironment might have a role in the lack of response. CTLA4 is an inhibitory checkpoint on activated T cells that is being studied as a therapeutic target in combination with anti-PD1 or anti-PDL1 therapies in advanced urothelial cancer. In locally advanced urothelial cancer, this combination approach has shown encouraging antitumour effects when administered pre-operatively. We believe that the presence of pre-existing intratumoural T cell immunity is not a prerequisite for response to combination therapy and that the additional value of CTLA4 blockade might involve the broadening of peripheral T cell priming, thereby transforming immunologically cold tumours into hot tumours.

Key points

  • CTLA4 blockade enhances the influx of CD8+ T cells towards the tumour.

  • The addition of anti-CTLA4 to anti-PD1 or anti-PDL1 could be particularly beneficial for immunologically ‘cold’ urothelial tumours, owing to its potential to broaden peripheral T cell priming.

  • Existing results require validation, but data suggest that the optimal dose for ipilimumab in combination with PD1 or PDL1 blockade in urothelial cancer is 3 mg/kg, as opposed to ipilimumab 1 mg/kg in other malignancies.

  • Results of phase III trials with first-line CTLA4 blockade are expected in the near future and could potentially change the treatment landscape of metastatic urothelial cancer.

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Fig. 1: Synergy between anti-CTLA4 and anti-PD1 and PDL1 in immunologically ‘cold’ urothelial cancers.

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Authors and Affiliations

  1. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands

    Chantal F. Stockem & Michiel S. van der Heijden

  2. Department of Genitourinary Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA

    Matthew D. Galsky

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C.F.S. researched data for the article. All authors contributed substantially to discussion of the content. C.F.S. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Michiel S. van der Heijden.

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M.D.G. declares research funding from Janssen, Merk, Dendreon, Novartis, Bristol-Myers Squibb, AZ and Genentech/Roche; consulting fees from BioMotiv, Janssen, Merk, Dendreon, GlaxoSmithKline, Lilly, Astellas, Genetech, BMS, Novartis, Pfizer, EMD Serono, AZ, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals and NuMab; and stock from Rapt Therapeutics. M.S.v.d.H. declares the following competing interests: research funding from Bristol-Myers Squibb, AstraZeneca, Roche and 4SC; and consultancy fees from Bristol-Myers Squibb, Merck, Roche, AstraZeneca, Seagen, Pfizer and Janssen (all paid to the Netherlands Cancer Institute). C.F.S. declares no competing interests.

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Stockem, C.F., Galsky, M.D. & van der Heijden, M.S. Turning up the heat: CTLA4 blockade in urothelial cancer. Nat Rev Urol 21, 22–34 (2024). https://doi.org/10.1038/s41585-023-00801-7

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