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Intraprostatic distribution and long-term follow-up after AdV-tk immunotherapy as neoadjuvant to surgery in patients with prostate cancer

Cancer Gene Therapy volume 20, pages 642–649 (2013)Cite this article

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Abstract

A phase I-II study to evaluate gene-mediated cytotoxic immunotherapy in newly diagnosed prostate cancer before radical prostatectomy was conducted in Monterrey, Mexico. First, to investigate delivery of adenovirus to the prostate, fluorescently labeled vector was injected into fresh prostatectomy specimens and distribution was visually analyzed. The optimal volume and site instillation was then used for transrectal ultrasound guided intraprostatic injection in 10 patients with adenocarcinoma scheduled for radical prostatectomy. Each received two apical and two basal 0.5 ml injections of AdV-tk for a total of 1 × 1011 vp followed by 14 days of prodrug. Nine patients continued to tumor resection: six high risk, one intermediate and two low risk. In vivo vector distribution was analyzed from the resected tissue of four patients. Patients were monitored for tumor progression and acute and long-term safety. For vector delivery, two apical and two basal injections of 0.5 ml led to optimal organ-wide distribution ex vivo and in vivo. Cytotoxicity was evidenced by transient rise in PSA and tumor histology. There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years. All six high-risk patients had positive surgical margins and one had seminal vesicle involvement. Despite slow PSA rise post surgery in three of these patients, none developed metastases. The intermediate- and low-risk patients had complete resections and none have progressed. In conclusion, in vivo transrectal ultrasound guided instillation of an adenoviral vector into four sites in the prostate was practical as an outpatient procedure, well tolerated and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities. Trends in PSA and disease progression conveyed the possibility of a sustained immune response against residual disease.

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Acknowledgements

We thank the patients who volunteer to give of their time and effort for these clinical trials in the hope of improving medical care for future generations. We also thank Dr Jesús Zacarías Villarreal Pérez, Minister of Health for the State of Nuevo Leon, who placed his support and effort to acquire the stringent regulatory approvals to import the vector and conduct the first gene therapy trial in the country. Supported in part by Grant No. R44CA124032 from the National Cancer Institute.

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Author notes

  1. H A Barrera-Saldaña and E Aguilar-Cordova: Co-principal investigators.

Authors and Affiliations

  1. Facultad de Medicina, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico

    A Rojas-Martínez, I Delgado-Enciso, R Ortiz-López & H A Barrera-Saldaña

  2. Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico

    A Rojas-Martínez & R Ortiz-López

  3. Department of Biochemistry, Universidad Autónoma de Nuevo León (UANL), Monterrey, Mexico

    A Rojas-Martínez, I Delgado-Enciso, R Ortiz-López & H A Barrera-Saldaña

  4. Advantagene, Inc., Auburndale, MA, USA

    A G Manzanera, L K Aguilar & E Aguilar-Cordova

  5. Texas Urology Specialists, Houston, TX, USA

    S W Sukin

  6. Department of Urology, Hospital Universitario, UANL, Monterrey, Mexico

    J Esteban-María, L Gomez-Guerra & R Garza-Guajardo

  7. Department of Oncology, Hospital Universitario, UANL, Monterrey, Mexico

    J F González-Guerrero

  8. Department of Pathology, Hospital Universitario, UANL, Monterrey, Mexico

    J P Flores-Gutiérrez

  9. Department of Radiology, Hospital Universitario, UANL, Monterrey, Mexico

    G Elizondo Riojas

  10. Facultad de Medicina, Universidad de Colima, Colima, Mexico

    I Delgado-Enciso

  11. Department of Radiation Oncology, The Methodist Hospital, Houston, TX, USA

    E B Butler

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  1. A Rojas-Martínez
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  2. A G Manzanera
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  12. L K Aguilar
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  14. H A Barrera-Saldaña
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  15. E Aguilar-Cordova
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Corresponding author

Correspondence to E Aguilar-Cordova.

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Competing interests

The authors identified as members of Advantagene, Inc. are employed by the company, which holds an interest in the AdV-tk technology. The remaining authors declare no conflict of interest.

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Rojas-Martínez, A., Manzanera, A., Sukin, S. et al. Intraprostatic distribution and long-term follow-up after AdV-tk immunotherapy as neoadjuvant to surgery in patients with prostate cancer. Cancer Gene Ther 20, 642–649 (2013). https://doi.org/10.1038/cgt.2013.56

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  • DOI: https://doi.org/10.1038/cgt.2013.56

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