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Intravesikale Therapie nicht muskelinvasiver Blasentumoren mit onkolytischen Vesikular-Stomatitisviren

Oncolytic vesicular stomatitis viruses as intravesical agents against non-muscle-invasive bladder cancer

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Zusammenfassung

Patienten mit Hochrisikoblasentumoren, die nicht auf eine BCG-Immuntherapie ansprechen, stellen eine therapeutische Herausforderung dar. Als Second-line-Therapie wird derzeit häufig eine Kombination aus BCG plus Interferon empfohlen. Da jedoch ein Großteil aggressiv wachsender Tumoren nicht sensibel auf Interferon reagiert, käme anstatt dessen der Einsatz onkolytischer Vesikular-Stomatitisviren (VSV) in Betracht, die speziell Interferon-refraktäre Tumorzellen angreifen. In vitro töteten sowohl Wildtyp-VSV als auch ein attenuierter Subtyp, der eine gesteigerte Tumorselektivität aufweist, bevorzugt aggressiv wachsende, Interferon-resistente Blasentumorzellen. Anschließende In-vivo-Versuche in einem von uns validierten orthotopen Mausmodell konnten die viel versprechende antikanzerogene Aktivität beider Viren nach intravesikaler Gabe eindrucksvoll bestätigen. Obwohl in diesem Modell immunkompromittierte Nacktmäuse verwendet werden, zeigte sich keine virale Toxizität. Zusammenfassend scheinen frühe klinische Studien zur intravesikalen Therapie mit VSV gerechtfertigt.

Abstract

Patients with high-risk bladder cancer who do not respond to bacillus Calmette-Guerin (BCG) immunotherapy represent a significant therapeutic challenge. The addition of interferon to BCG has recently evolved as a second-line treatment option; however, many high-grade tumors are nonresponsive to interferon. Thus, replication-competent oncolytic vesicular stomatitis viruses (VSV) that selectively target interferon-refractory tumors are promising intravesical agents. In vitro, wild-type VSV as well as a mutant variant (AV3) that has an impaired ability to shut down innate immunity preferentially killed undifferentiated, interferon-nonresponsive bladder cancer cells. Testing of these viruses in an orthotopic murine model of high-grade bladder cancer, which we have recently validated, revealed that both AV3 and wild-type VSV significantly inhibited orthotopic tumor growth. Despite the use of immunocompromised nude mice, there was no evidence of toxicity. In conclusion, VSV instillation therapy demonstrated strong antitumor activity and safety in an orthotopic model of high-risk disease. These findings provide preclinical proof-of-principle for the intravesical use of VSV, especially in interferon-refractory patients.

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Abbreviations

BCG:

Bacillus Calmette-Guérin

BLI:

Biolumineszenzbildgebung

VSV:

Vesicular-Stomatitisvirus

IFN:

Interferon

pfu:

plaqueformende Einheiten

ph/s:

Photonen pro Sekunde

WT:

Wildtyp

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung hin: John Bell ist Mitbegründer von Jennerex Biotherapeutics, San Francisco, CA, einer Firma, die onkolytische Vaccinia-Viren entwickelt. Es besteht kein Interessenkonflikt. Der Beitrag ist unabhängig und produktneutral.

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Authors and Affiliations

  1. Prostate Centre, Vancouver General Hospital, Vancouver , BC, Kanada

    B.A. Hadaschik, K. Zhang, A.I. So, P.S. Rennie & M.E. Gleave

  2. Urologische Klinik, Johannes-Gutenberg-Universität Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland

    B.A. Hadaschik & J.W. Thüroff

  3. Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, ON, Kanada

    J.C. Bell

Authors
  1. B.A. Hadaschik
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  2. K. Zhang
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  3. A.I. So
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  4. J.C. Bell
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  5. J.W. Thüroff
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  6. P.S. Rennie
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  7. M.E. Gleave
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Correspondence to B.A. Hadaschik.

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Hadaschik, ., Zhang, K., So, A. et al. Intravesikale Therapie nicht muskelinvasiver Blasentumoren mit onkolytischen Vesikular-Stomatitisviren. Urologe 47, 1145–1151 (2008). https://doi.org/10.1007/s00120-008-1827-x

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  • DOI: https://doi.org/10.1007/s00120-008-1827-x

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