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

Abstract

In this study, we investigated the safety and efficacy in cancer patients of a single intra-tumor injection of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene (AdV/TK) followed by systemic administration of ganciclovir (GCV). In 18 patients with malignant tumors refractory to standard treatment, AdV/TK was injected on day 1 with dose escalation from 2.5 Â 10 11 to 1 Â 10 12 virus particles (VP), and GCV (5 mg kg À1 ) was delivered intravenously every 12 h from days 2 to 15. The most common treatment-related toxicities were transient fever (10/18) and local injection site reaction (10/18), and most adverse events were WHO grade I/II. Anti-adenovirus antibody levels increased continuously during treatment, but anti-HSV antibody levels remained stable. One patient had a PR at the injection site but PD was found in the primary site (lung cancer), one patient with fibrosarcoma of the neck had an MR, five patients had SD, and 10 patients had PD. In conclusion, AdV/TK followed by GCV can be administered safely to Chinese cancer patients, and achieved a local response with few environmental effects. Because the response was localized, single regional tumor relapse, especially after radiation, may be an indication for this suicide gene therapy.

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

“…Most commonly investigated anticancer prodrugs, such as ganciclovir, 5-fluorocytosine (5-FC), 4-[N,N-bis(2-iodoethyl) amino] phenoxycarbonyl L-glutamic acid (ZD2767P) and 5-(azaridin-1-yl) 2,4-dinotrobenzamide (CB1954) are chemically synthesized ex vivo and then directly administered to patients. 28,[34][35][36] By contrast, SN-38G is generated in vivo by UDPglucuronosyl transferases acting on SN-38, the active metabolite of CPT-11. 8 In vivo generation of SN-38G may be particularly advantageous as hydrophilic glucuronide metabolites are rapidly eliminated from the circulation.…”

Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus

“…Future treatment efficacy of armed and targeted MV for HNSCC might further be improved in a multimodal approach with conventional therapies including radio-therapy and/or platinum. To date, first clinical studies using oncolytic viruses in HNSCC were conducted with a replication-selective adenovirus, combined with radiotherapy, 39 and with herpes simplex virus 40,41 in Phase I/II studies in combination with radiotherapy and cisplatin in untreated stage III/IV HNSCC. 7 First results suggested safety and some evidence of efficacy of these replicative oncolytic viruses.…”

Oncolytic viruses: From bench to bedside with a focus on safety

“…Shedding of crHAdVs from injection sites and patient excretions, although not always reported, has been observed in several (pre) clinical trials, and increases with higher doses and systemic administration. 49,[58][59][60][61][62][63][64] Shedding of HAdV vectors could result in homologous recombination between AdVs of the same subgroup, which occurs with high efficiency during growth in co-infected cultured cells, and there is evidence of recombination events in humans as well. [65][66][67] Theoretically, homologous recombination between wildtype AdVs and recombinant crHAdVs could lead to new wildtype AdVs that e.g.…”