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  • Review Article
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Immune-based therapies in penile cancer

Nature Reviews Urology volume 19, pages 457–474 (2022)Cite this article

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Abstract

Penile cancer is a rare genitourinary malignancy that is associated with poor outcomes and severely limited therapeutic options that are generally non-curative when used to treat localized disease with high-risk features or advanced disease. To address the unmet need for treatment modalities with increased effectiveness, immune-based therapies such as immune-checkpoint blockade, human papilloma virus (HPV)-directed vaccines and adoptive T cell therapies have emerged as potential treatment options for advanced penile cancer. A diverse array of immune cells such as cytotoxic T lymphocytes (CTLs), tumour-associated macrophages and myeloid-derived suppressor cells have been shown to infiltrate penile cancer tumours, with distinct immune landscapes being demonstrated in HPV-positive compared with HPV-negative tumours. Study results have also demonstrated the prognostic value of immune cells such as tumour-associated macrophages, immune markers such as programmed death ligand-1, and HPV-status in penile cancer. Taken together, these findings underscore the clinical relevance of the tumour immune microenvironment as a source of both prognostic indicators and potential therapeutic targets for immune-based therapies. Current evidence regarding the safety and efficacy of immune-based therapies is limited in penile cancer, but a number of clinical and preclinical studies are ongoing to evaluate these therapies in this disease based on promising results from studies in other malignancies, including other squamous cell carcinomas. In addition, an opportunity exists to combine immune-based therapies with existing lines of systemic therapy to offer the most benefit to patients with advanced penile cancer. Future work should focus on expansion of preclinical models for immune-based drug discovery.

Key points

  • The immune landscape of penile cancer is defined by unique patterns of immune cell infiltration that also serve as prognostic indicators of metastasis and survival.

  • Human papilloma virus (HPV) infection status can be used to stratify patients into two groups with differing tumour immune microenvironments (TIMEs) based on key markers such as programmed death-ligand 1.

  • Immune-based therapies including immune-checkpoint blockade, adoptive T cell therapies, and HPV-targeting therapeutic vaccines are each promising candidate therapies, although these treatments are largely unexplored in penile cancer; however, they are currently being evaluated prospectively.

  • The optimal management of locally advanced penile cancer might involve a multimodal approach that combines immune-based therapies with chemotherapeutic and/or targeted agents early in the disease course followed by surgery.

  • Preclinical models that will improve understanding of the TIME and the mechanisms underlying responses to immune-based therapies are needed.

  • In this rare disease context, future preclinical and clinical work on immune-based therapies will benefit from the centralization of care and the pooling of collaborative scientific knowledge and resources.

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Fig. 1: The immune landscape of penile cancer.
Fig. 2: Potential immune-based therapies for penile cancer.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

    Vidhu B. Joshi

  2. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Philippe E. Spiess & Jad Chahoud

  3. IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy

    Andrea Necchi

  4. Vita-Salute San Raffaele University, Milan, Italy

    Andrea Necchi

  5. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Curtis A. Pettaway

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  2. Philippe E. Spiess
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  4. Curtis A. Pettaway
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  5. Jad Chahoud
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Contributions

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

Corresponding author

Correspondence to Jad Chahoud.

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Competing interests

P.E.S. maintains leadership positions of relevance as a member of the NCCN penile cancer panel, President of the Global Society of Rare GU Tumors and ASCO/EAU Penile Cancer Panel Member. A.N. serves as Vice-President of the Global Society of Rare GU Tumors (GSRGT) and is an ASCO/EAU Penile Cancer Panel Member. C.A.P. is an Editorial Consultant for the ‘UpToDate’ penile cancer series published by Wolters Kluwer. J.C. reports that he provided advisory board consultations for Pfizer, Aveo and Exelixis. V.B.J. declares no competing interests.

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Joshi, V.B., Spiess, P.E., Necchi, A. et al. Immune-based therapies in penile cancer. Nat Rev Urol 19, 457–474 (2022). https://doi.org/10.1038/s41585-022-00617-x

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