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

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.

Cotargeting tumor and tumor endothelium effectively inhibits the growth of human prostate cancer in adenovirus-mediated antiangiogenesis and oncolysis combination therapy

“…44,45 The safety of an adenoviral vector carrying OC promoter-driven HSV-TK gene was also recently demonstrated in a Phase I clinical trial. 46 The major side effect of high-dose vitamin D administration is hypercalcemia, which would jeopardize its clinical utility. Although the vitamin D 3 analogue Ro 25-9022, used in the present study, has not been tested at the maximum tolerated dose, when mice treated with 4 ng of Ro 25-9022 twice per week were compared with untreated mice, they showed only a mild side effect, a less than 10% body weight reduction for a period of 3 weeks.…”

Angiotensin type 2 receptor–mediated apoptosis of human prostate cancer cells

“…Chemotherapy has been of limited value because most patients do not respond to secondary manipulations after developing hormone-refractory disease (3). Significant advances have been made in gene therapy, and several clinical trials have been in progress over recent years as a result of developments in molecular and cell biology (4)(5)(6)(7)(8)(9)(10). Thus, it is important to develop novel therapeutic approaches and to explore the use of gene therapy as an alternative treatment modality.…”

Hopes and Disillusions in Therapeutic Targeting of Intercellular Communication in Cancer.

“…In this trial, an adenovirus vector carrying osteocalcin promoter-driven HSVtk was used to target both prostate cancer cells and their neighboring stromal cells and valacyclovir, another anti herpetic prodrug converted to aciclovir, was given orally. The results showed a good tolerance with no serious adverse events but with local cell death in treated lesions in 63.6% of patients (Kubo et al 2003). In another clinical phase I/II study, 36 prostate cancer patients with local recurrence after radiotherapy which received single or repeated cycles of adenoviral vector-mediated HSVtk/GCV intraprostatic gene therapy (Miles et al 2001) showed no significant side effects and a significant increase in biological responses such as the mean serum PSA-doubling time (PSADT), prostate-specific antigen recurrence (PSAR), return to initial PSA (TR-PSA), and activated CD8(+) T cells present in the peripheral blood.…”