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Don't run before you can walk

Nature Reviews Urology volume 9, page 602 (2012)Cite this article

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We greatly appreciated the Nature Reviews Urology News & Views article by Sharma and Logothetis (Prostate cancer: Combination of vaccine plus ipilimumab—safety and toxicity. Nat. Rev. Urol. 9, 302–303; 2012.),1 fully agreeing with the authors' conclusions regarding the relevance of novel immunotherapeutics, but also sharing their concerns regarding the severe toxicity caused by cytotoxic T-lymphocyte protein 4 (CTLA4) blockade. In response to this article, we wish to offer a few additional insights into the use of immunotherapy for prostate cancer and some possible suggestions for maximizing the efficacy of ipilimumab, while maintaining an acceptable drug safety profile.

Although combination therapy (ipilimumab plus cancer vaccine) seems to have an adverse-effect profile comparable to that of ipilimumab alone,2,3 it is our opinion that combined treatment could introduce an additional level of unpredictable toxicity. In fact, vaccination could trigger bystander (self) crossreactive immune responses that might then be expanded by CTLA4-blockade, with an uncontrollable and unpredictable magnification of autoimmune reactions. Cellular vaccines based on allogenic prostate carcinoma cells might activate immune responses against normal epithelial antigens, which could exacerbate autoimmunity against normal mucosae and skin (upon amplification by ipilimumab).3 Viral-vector-based vaccines, on the other hand, could trigger T or B cells to crossreact with mimicking self-antigenic determinants (frequently identified in viral infections), leading to increased autoimmune toxicity.2,4,5 Thus, we speculate that ipilimumab should be combined with cancer vaccines that specifically target antigens expressed uniquely or prevalently by tumour cells. Whole proteins or long peptides derived from tumour-specific antigens—such as cancer-testis proteins6 or molecules linked to neoplastic transformation7,8—are appropriate for such a role.

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Authors and Affiliations

  1. Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133, Italy

    Licia Rivoltini & Chiara Castelli

  2. Prostate Cancer Programme, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133, Italy

    Sergio Villa & Riccardo Valdagni

  3. Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133, Italy

    Andrea Marrari

Authors
  1. Licia Rivoltini
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  2. Andrea Marrari
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Correspondence to Licia Rivoltini.

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The authors declare no competing financial interests.

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Rivoltini, L., Marrari, A., Castelli, C. et al. Don't run before you can walk. Nat Rev Urol 9, 602 (2012). https://doi.org/10.1038/nrurol.2012.103-c1

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