Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer

Hiroyuki Kubo, Thomas Gardner, Yoshitaka Wada, Kenneth S. Koeneman, Akinobu Gotoh, Ling Yang, Chinghai Kao, So Dug Lim, Mahul B. Amin, Hua Yang, Margaret E. Black, Shigeji Matsubara, Masayuki Nakagawa, Jay Y. Gillenwater, Haiyen E. Zhau, Leland W K Chung

Research output: Contribution to journalArticle

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Abstract

Osteocalcin (OC), a major noncollagenous bone matrix protein, is expressed prevalently in prostate cancer epithelial cells, adjacent fibromuscular stromal cells, and osteoblasts in locally recurrent prostate cancer and prostate cancer bone metastasis [Matsubara, S., Wada, Y., Gardner, T.A., Egawa, M., Park, M.S., Hsieh, C.L., Zhau, H.E., Kao, C., Kamidono, S., Gillenwater, J.Y., and Chung, L.W. (2001). Cancer Res. 61, 6012-6019]. We constructed an adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase (Ad-OC-hsv-TK) to cotarget prostate cancer cells and their surrounding stromal cells. A phase I dose escalation clinical trial of the intralesional administration of Ad-OC-hsv-TK followed by oral valacyclovir was conducted at the University of Virginia (Charlottesville, VA) in 11 men with localized recurrent and metastatic hormone-refractory prostate cancer (2 local recurrent, 5 osseous metastasis, and 4 lymph node metastasis) in order to determine the usefulness of this vector for the palliation of androgen-independent prostate cancer metastasis. This is the first clinical trial in which therapeutic adenoviruses are injected directly into prostate cancer lymph node and bone metastasis. Results show that (1) all patients tolerated this therapy with no serious adverse events; (2) local cell death was observed in treated lesions in seven patients (63.6%) as assessed by TUNEL assay, and histomorphological change (mediation of fibrosis) was detected in all posttreated specimens; (3) one patient showed stabilization of the treated lesion for 317 days with no alternative therapy. Of the two patients who complained of tumor-associated symptoms before the treatment, one patient with bone pain had resolution of pain, although significant remission of treated lesions was not observed by image examination; (4) CD8-positive T cells were predominant compared with CD4-positive T cells, B cells (L26 positive), and natural killer cells (CD56 positive) in posttreated tissue specimens; (5) levels of HSV TK gene transduction correlated well with coxsackie-adenovirus receptor expression but less well with the titers of adenovirus injected; and (6) intrinsic OC expression and the efficiency of HSV TK gene transduction affected the levels of HSV TK protein expression in clinical specimens. Our data suggest that this form of gene therapy requires further development for the treatment of androgen-independent prostate cancer metastasis although histopathological and immunohistochemical evidence of apoptosis was observed in the specimens treated. Further studies including the development of viral delivery will enhance the efficacy of Ad-OC-hsv-TK.

Original languageEnglish
Pages (from-to)227-241
Number of pages15
JournalHuman Gene Therapy
Volume14
Issue number3
DOIs
StatePublished - Feb 10 2003

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Thymidine Kinase
Osteocalcin
Simplexvirus
Adenoviridae
Prostatic Neoplasms
Clinical Trials
Hormones
Neoplasm Metastasis
valacyclovir
Stromal Cells
Androgens
Coxsackie and Adenovirus Receptor-Like Membrane Protein
Lymph Nodes
T-Lymphocytes
Bone and Bones
Pain
Bone Neoplasms
Bone Matrix
In Situ Nick-End Labeling
Therapeutics

ASJC Scopus subject areas

  • Genetics

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Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. / Kubo, Hiroyuki; Gardner, Thomas; Wada, Yoshitaka; Koeneman, Kenneth S.; Gotoh, Akinobu; Yang, Ling; Kao, Chinghai; Lim, So Dug; Amin, Mahul B.; Yang, Hua; Black, Margaret E.; Matsubara, Shigeji; Nakagawa, Masayuki; Gillenwater, Jay Y.; Zhau, Haiyen E.; Chung, Leland W K.

In: Human Gene Therapy, Vol. 14, No. 3, 10.02.2003, p. 227-241.

Research output: Contribution to journalArticle

Kubo, H, Gardner, T, Wada, Y, Koeneman, KS, Gotoh, A, Yang, L, Kao, C, Lim, SD, Amin, MB, Yang, H, Black, ME, Matsubara, S, Nakagawa, M, Gillenwater, JY, Zhau, HE & Chung, LWK 2003, 'Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer', Human Gene Therapy, vol. 14, no. 3, pp. 227-241. https://doi.org/10.1089/10430340360535788
Kubo, Hiroyuki ; Gardner, Thomas ; Wada, Yoshitaka ; Koeneman, Kenneth S. ; Gotoh, Akinobu ; Yang, Ling ; Kao, Chinghai ; Lim, So Dug ; Amin, Mahul B. ; Yang, Hua ; Black, Margaret E. ; Matsubara, Shigeji ; Nakagawa, Masayuki ; Gillenwater, Jay Y. ; Zhau, Haiyen E. ; Chung, Leland W K. / Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. In: Human Gene Therapy. 2003 ; Vol. 14, No. 3. pp. 227-241.
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AU - Kubo, Hiroyuki

AU - Gardner, Thomas

AU - Wada, Yoshitaka

AU - Koeneman, Kenneth S.

AU - Gotoh, Akinobu

AU - Yang, Ling

AU - Kao, Chinghai

AU - Lim, So Dug

AU - Amin, Mahul B.

AU - Yang, Hua

AU - Black, Margaret E.

AU - Matsubara, Shigeji

AU - Nakagawa, Masayuki

AU - Gillenwater, Jay Y.

AU - Zhau, Haiyen E.

AU - Chung, Leland W K

PY - 2003/2/10

Y1 - 2003/2/10

N2 - Osteocalcin (OC), a major noncollagenous bone matrix protein, is expressed prevalently in prostate cancer epithelial cells, adjacent fibromuscular stromal cells, and osteoblasts in locally recurrent prostate cancer and prostate cancer bone metastasis [Matsubara, S., Wada, Y., Gardner, T.A., Egawa, M., Park, M.S., Hsieh, C.L., Zhau, H.E., Kao, C., Kamidono, S., Gillenwater, J.Y., and Chung, L.W. (2001). Cancer Res. 61, 6012-6019]. We constructed an adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase (Ad-OC-hsv-TK) to cotarget prostate cancer cells and their surrounding stromal cells. A phase I dose escalation clinical trial of the intralesional administration of Ad-OC-hsv-TK followed by oral valacyclovir was conducted at the University of Virginia (Charlottesville, VA) in 11 men with localized recurrent and metastatic hormone-refractory prostate cancer (2 local recurrent, 5 osseous metastasis, and 4 lymph node metastasis) in order to determine the usefulness of this vector for the palliation of androgen-independent prostate cancer metastasis. This is the first clinical trial in which therapeutic adenoviruses are injected directly into prostate cancer lymph node and bone metastasis. Results show that (1) all patients tolerated this therapy with no serious adverse events; (2) local cell death was observed in treated lesions in seven patients (63.6%) as assessed by TUNEL assay, and histomorphological change (mediation of fibrosis) was detected in all posttreated specimens; (3) one patient showed stabilization of the treated lesion for 317 days with no alternative therapy. Of the two patients who complained of tumor-associated symptoms before the treatment, one patient with bone pain had resolution of pain, although significant remission of treated lesions was not observed by image examination; (4) CD8-positive T cells were predominant compared with CD4-positive T cells, B cells (L26 positive), and natural killer cells (CD56 positive) in posttreated tissue specimens; (5) levels of HSV TK gene transduction correlated well with coxsackie-adenovirus receptor expression but less well with the titers of adenovirus injected; and (6) intrinsic OC expression and the efficiency of HSV TK gene transduction affected the levels of HSV TK protein expression in clinical specimens. Our data suggest that this form of gene therapy requires further development for the treatment of androgen-independent prostate cancer metastasis although histopathological and immunohistochemical evidence of apoptosis was observed in the specimens treated. Further studies including the development of viral delivery will enhance the efficacy of Ad-OC-hsv-TK.

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