Suicide Gene Therapy With Adenoviral Delivery of HSV-tK Gene for Patients With Local Recurrence of Prostate Cancer After Hormonal Therapy

Abstract

We conducted a Phase I study of in situ herpes simplex virus thymidine kinase (HSV-tk) plus ganciclovir (GCV) gene therapy, which was approved by the Japanese government as the first prostate cancer gene therapy trial. Major inclusion criteria were local recurrence of prostate cancer after hormonal therapy and no metastasis. Adv.HSV-tk was injected directly into the prostate in escalating doses from 10(9) to 10(10) infection units, followed by intravenous administration of GCV for 14 days. Eight patients received nine courses of this gene therapy. The detection of vector DNA in blood/urine was only transient and no remarkable adverse events were observed in any patient. With regard to clinical response, significant prolongation of the median serum prostate-specific antigen (PSA) doubling time from 2.9 to 6.2 months (P = 0.041) was detected. In five patients (six injections), a clear decrease of PSA values was observed. One patient showed repeated clinical response after repeated injections. Serum cytokine analysis showed no notable changes after treatment. Fluorescence-activated cell sorting analysis also showed no influence on phenotypic distribution in peripheral blood samples, except for an increasing trend of CD8(+)/HLA-DR(+) after therapy. This study confirmed the safety profile and possibility of clinical response at the surrogate marker level in a clinical trial of HSV-tk gene therapy for hormone-refractory prostate cancer.

Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors

“…[8][9][10][11][12][13][14] There have been no reports evaluating this agent in NPC or head and neck cancer, both of which are common among Chinese people, often relapse locally and are often resistant to radiotherapy and chemotherapy. In this study, the majority of subjects had been diagnosed with NPC or head and neck cancer.…”

“…4,5 One attractive feature of the HSV tk/GCV system is the presence of a 'bystander effect' and the induction of antitumor immune responses. [6][7][8] On account of shortages of the retrovirus vector, researchers have recently begun to use recombinant replication-incompetent adenoviruses (Ad) as vectors to transfer different target genes including HSV tk. Ad-expressing HSV tk (AdV/TK)/GCV has shown evidence of in vitro and in vivo efficacy in many different animal models of malignancy.…”

Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo

“…Therapeutic combinations such as the herpes simplex virus thymidine kinase (HSVtk) gene and its prodrug ganciclovir (GCV), or bacterial nitroreductase (NTR) and its prodrug CB1954, produce toxic metabolites that are freely diffusible and able to kill neighboring cells via a 'bystander effect'. 13,14 Both systems are well characterized and have been investigated in clinical trials, [15][16][17] but have not been compared in parallel under hypoxic conditions under the control of different transcriptional promoters. The combination of transcriptional regulation, hypoxia-selective HREs and adenoviral delivery of prodrug-activating genes therefore provides great potential for selective targeting of hypoxic regions within solid tumors.…”

Regulation of gene expression in prostate cancer cells with an artificially constructed promoter responsive to radiation

“…[8][9][10] However, gene therapy does not still become a general procedure for prostate cancer treatment, because of its associated challenges, including low transduction efficiency, low specificity to the target tissue and adverse side effects of the cytotoxicity of a therapeutic gene product.…”