A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma

Abstract

The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10 10 to 2 Â 10 12 viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 Â 10 12 vp per patient.

Short-Term Intratumoral Interleukin-12 Expressed from an Alphaviral Vector Is Sufficient to Induce an Efficient Antitumoral Response Against Spontaneous Hepatocellular Carcinomas

“…Our use of a clinically relevant animal model that closely resembles human HCCs warrants interest from a translational research perspective. Although both the long-term and short-term expression vectors that we used in this study showed similar effects, the latter has some intrinsic advantages that could favor its clinical use: (i) alphaviral vectors can be produced at high titers and have been tested in clinical trials, showing a high degree of safety (Bernstein et al, 2009;Morse et al, 2010); (ii) phase I clinical trials have proven the feasibility and low toxicity of intratumoral injection of viral vectors into HCC nodules (Sangro et al, 2004(Sangro et al, , 2010Penuelas et al, 2005); (iii) short-term IL-12 and IFN-c expression was sufficient to achieve potent therapeutic effects, which could reduce the toxicity associated with the long-term expression of these cytokines; and finally, (iv) although improbable, a long-term expressing DNA vector such as pTonL2(T)-mIL12 could integrate into the genome of healthy liver cells, while the RNA SFV-IL-12 vector would quickly disappear because of the apoptosis of infected cells concomitant with tumor regression. All of these properties, together with the high antitumoral efficacy already observed in other clinically relevant models of spontaneous HCC (Rodriguez-Madoz et al, 2009), indicate that SFV-IL-12 could be clinically useful.…”

Progress and problems with the use of suicide genes for targeted cancer therapy

“…In patients who received high doses, partial tumor stabilization and intratumoral necrosis was also reported. The authors confirmed the safety and feasibility of such local therapy in patients with hepatocellular carcinoma [74]. As the first in this category, Cerepro ® (Sitimagene ceradenovec) is an adenoviral vector-based HSVTK/GCV system with the potential for the treatment of high grade glioma.…”

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

“…13 Several clinical trials support the feasibility of this approach. [14][15][16][17][18] However, HSV-tk is a viral gene and may induce an unwanted immune response against functionally desirable T cells. Activation of the system also requires a clinically useful prodrug (like ganciclovir) to be administered for cell destruction.…”