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Neoadjuvant lutetium PSMA, the TIME and immune response in high-risk localized prostate cancer

Nature Reviews Urology (2024)Cite this article

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Abstract

High-risk localized prostate cancer remains a lethal disease with high rates of recurrence, metastases and death, despite attempts at curative local treatment including surgery. Disease recurrence is thought to be a result of failure of local control and occult micrometastases. Neoadjuvant strategies before surgery have been effective in many cancers, but, to date, none has worked in this setting for prostate cancer. Prostate-specific membrane antigen (PSMA)-based theranostics is an exciting and rapidly evolving field in prostate cancer. The novel intravenous radionuclide therapy, [177Lu]Lu-PSMA-617 (lutetium PSMA) has been shown to be effective in treating men with metastatic castration-resistant prostate cancer, targeting cells expressing PSMA throughout the body. When given in a neoadjuvant setting, lutetium PSMA might also improve long-term oncological outcomes in men with high-risk localized disease. A component of radiotherapy is potentially an immunogenic form of cancer cell death. Lutetium PSMA could cause cancer cell death, resulting in release of tumour antigens and induction of a tumour-specific systemic immune response. This targeted radioligand treatment has the potential to treat local and systemic tumour sites by directly targeting cells that express PSMA, but might also act indirectly via this systemic immune response. In selected patients, lutetium PSMA could potentially be combined with systemic immunotherapies to augment the antitumour T cell response, and this might produce long-lasting immunity in prostate cancer.

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Fig. 1: Radiotherapy induces immunogenic cell death and T cell responses to tumour antigen.
Fig. 2: Potential for an immunogenic response to systemic lutetium PSMA treatment.

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Acknowledgements

The authors acknowledge support from the Prostate Cancer Foundation through their Young Investigator Award. The LuTectomy trial was funded by the Movember Foundation, the Australian Government Medical Research Future Fund (MRFF) with contribution from the EJ Whitten Foundation and Novartis. PSMA-617 was supplied by Novartis and no carrier added 177Lu by the Australian Nuclear Science and Technology Organisation (ANSTO). Finally, they thank the patients who participated in the LuTectomy clinical trial and the staff involved in the study from numerous departments at the Peter MacCallum Cancer Centre, Melbourne.

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Author notes

  1. These authors contributed equally: Declan G. Murphy, Paul J. Neeson.

Authors and Affiliations

  1. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia

    Renu S. Eapen, Scott G. Williams, Sean Macdonald, Lewis Au & Paul J. Neeson

  2. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia

    Renu S. Eapen, Scott G. Williams, Sean Macdonald, Simon P. Keam, Nathan Lawrentschuk, Lewis Au, Michael S. Hofman, Declan G. Murphy & Paul J. Neeson

  3. Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Peter MacCallum Cancer Centre, Melbourne, Australia

    Renu S. Eapen, Scott G. Williams, Michael S. Hofman & Declan G. Murphy

  4. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia

    Renu S. Eapen, Nathan Lawrentschuk & Declan G. Murphy

  5. Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

    Scott G. Williams

  6. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

    Lewis Au

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Contributions

R.S.E., M.S.H., D.G.M. and P.J.N. researched data for the article. R.S.E., S.G.W., S.P.K., M.S.H., D.G.M. and P.J.N. contributed substantially to discussion of the content. R.S.E., S.G.W., M.S.H., D.G.M. and P.J.N. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Renu S. Eapen or Paul J. Neeson.

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Competing interests

R.S.E. is supported through the Prostate Cancer Foundation (PCF) Michael and Lori Milken Young Investigator Award. She reports honorarium for advisory board and speaker activity from Janssen, Bayer, Astellas, AstraZeneca, Ipsen, MSD, MDI and Amgen. L.A. reports honorarium from Bristol Myers Squibb (BMS), Eisai and Ipsen. M.S.H. reports philanthropic/government grant support from PCF funded by CANICA Oslo Norway, Peter MacCallum Foundation, Medical Research Future Fund, NHMRC Investigator Grant, Movember, US Department of Defence and the Prostate Cancer Foundation of Australia. D.G.M. reports reimbursement for advisory board and speaker activity from Janssen, Bayer, AstraZeneca, Ipsen and Ferring. P.J.N. reports research funding from BMS, Roche Genentech, MSD, Crispr therapeutics and Allergan. There was no impact on this work from other interests.

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Nature Reviews Urology thanks Riccardo Laudicella and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Eapen, R.S., Williams, S.G., Macdonald, S. et al. Neoadjuvant lutetium PSMA, the TIME and immune response in high-risk localized prostate cancer. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00913-8

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