Intratumoral Adenovirus-Mediated Suicide Gene Transfer for Hepatic Metastases from Colorectal Adenocarcinoma: Results of a Phase I Clinical Trial

Abstract

Animal studies have shown that direct injection of an adenoviral vector (Adv.RSV-tk) expressing the herpes thymidine kinase gene into established tumors in the liver, followed by systemic ganciclovir administration, was effective in inducing tumor necrosis. Toxicities were minimal at therapeutically effective vector doses, although severe hepatic necroinflammation was seen at much higher supratherapeutic doses. We conducted a clinical phase I trial in patients with metastatic colorectal adenocarcinoma in the liver to assess the safety of intratumoral Adv.RSV-tk injection (escalating doses) followed by intravenous ganciclovir (fixed dose). The vector was injected into a metastatic tumor in the liver under local anesthesia by percutaneous needle placement with concurrent ultrasonographic monitoring to prevent injection or leakage into adjacent normal liver structures. We treated 16 patients in five dose level cohorts of Adv.RSV-tk, from 1.0x10(10) to 1.0x10(13) virus particles per patient. Hepatic toxicities were low, with transient grade 1 elevations in serum aminotransferase levels in 3 of 16 patients. Other toxicities were also transient: grade 2-3 fevers in 5 of 16 patients, grade 3 thrombocytopenia in 1 of 16 patients, and grade 2 leucopenia in 3 of 16 patients. These results indicate that Adv.RSV-tk can be safely administered by percutaneous intratumoral injection in patients with hepatic metastases at doses up to 1.0x10(13) virus particles per patient, and can provide the basis for future clinical trials involving intratumoral adenoviral vector injection.

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection

“…Preliminary studies in humans have shown that gene delivery with viral vectors can be done safely, given either intraarterially or by direct tumor injection. [39][40][41] Most gene therapy strategies seek to redirect the host immune response against malignant cells by delivering immunostimulatory agents in proximity to putative tumor antigens. 23,42,43 Many approaches attempt to induce expression of such molecules directly within the target tumor using replication incompetent viral vectors.…”

“…Indeed, injection of NV1042 markedly increased the population of CD4(+) and CD8(+) lymphocytes within the tumor, as has been observed in previous studies. 39,41 Furthermore, in prior work with these viruses in a model of squamous cell carcinoma, depletion of CD4(+) and CD8(+) lymphocytes abrogated the enhanced antitumor efficacy of NV1042 compared with NV1023. 39 Not surprisingly, NV1023 injection reduced the parent tumor volume compared to control, although this reduction was less than that effected by NV1042.…”

“…39,41 Furthermore, in prior work with these viruses in a model of squamous cell carcinoma, depletion of CD4(+) and CD8(+) lymphocytes abrogated the enhanced antitumor efficacy of NV1042 compared with NV1023. 39 Not surprisingly, NV1023 injection reduced the parent tumor volume compared to control, although this reduction was less than that effected by NV1042. Additionally, however, NV1023 did offer some protection against cancer recurrence after resection and rechallenge, although the difference was not significantly different from control animals and was not as striking as that seen with NV1042.…”

Prolonged and inducible transgene expression in the liver using gutless adenovirus: A potential therapy for liver cancer

“…25,26 Therapy of established tumors with first generation adenoviruses encoding interleukin-12 (IL-12) has been very effective in different animal models of transplanted tumors. [27][28][29] However, although in our phase I/II study, the intratumor administration of firstgeneration adenovirus encoding human IL-12 (hIL-12) has been well tolerated, the antitumor effects were quite weak.…”

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

“…11 The experience using Ad.TK/GCV in patients with advanced HCC is scarce, 30 and for secondary liver tumors the results from a single clinical trial in patients with metastatic colorectal carcinoma have been published. 31 In the latter, authors demonstrated the safety of direct injection of up to 10 13 vp of an adenovirus coding for TK into metastatic colorectal liver tumors followed by GCV treatment; nevertheless no objective antitumor responses were reported.…”