Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells

Abstract

Intratumoral implantation of murine cells modified to produce retroviral vectors containing the herpes simplex virus-thymidine kinase (HSV-TK) gene induces regression of experimental brain tumors in rodents after ganciclovir (GCV) administration. We evaluated this approach in 15 patients with progressive growth of recurrent malignant brain tumors. Antitumor activity was detected in five of the smaller tumors (1.4 +/- 0.5 ml). In situ hybridization for HSV-TK demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated limited gene transfer to tumors, suggesting that indirect, "bystander," mechanisms provide local antitumor activity in human tumors. However, the response of only very small tumors in which a high density of vector-producing cells had been placed suggests that techniques to improve delivery and distribution of the therapeutic gene will need to be developed if clinical utility is to be achieved with this approach.

A systematic review and meta‐analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

“…This is exemplified by two unsuccessful phase III randomized controlled trials of gene therapy16, 17 and variable responses in other smaller clinical studies 6, 18, 19, 20, 21…”

Direct evidence for the absence of intercellular trafficking of VP22 fused to GFP or to the herpes simplex virus thymidine kinase

“…In particular, it is a strong limitation for the treatment of solid tumors with retroviral vectors using the herpes simplex virus thymidine kinase (TK)/ganciclovir (GCV) strategy. 1,2 In this suicide gene therapy approach, the TK enzyme transforms the nucleosidic analog GCV into GCV-monophosphate, which is subsequently converted into the di-and triphosphate forms by cellular kinases. 3 Then, the GCVtriphosphate is incorporated into elongating DNA, which can lead to the death of tumor cells.…”

“…[8][9][10] Despite very encouraging preclinical trials, this strategy has so far not shown great success in patients. The efficiency of TK gene transfer with retroviral vectors reported in some clinical trials was extremely low, 1,2 and it could in part explain the disappointing results observed in patients. 1,11 We could assume that it should be possible to increase the efficiency of gene transfer by using the latest generation of packaging cell lines that produce high-titer recombinant retroviruses.…”

“…The efficiency of TK gene transfer with retroviral vectors reported in some clinical trials was extremely low, 1,2 and it could in part explain the disappointing results observed in patients. 1,11 We could assume that it should be possible to increase the efficiency of gene transfer by using the latest generation of packaging cell lines that produce high-titer recombinant retroviruses. 12,13 Another means to render the TK/GCV strategy more potent would be to increase the BE in order to kill more untransduced cancer cells.…”

Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a BH3-only cell death activator

“…3 Results of clinical trials of HSV-tk/GCV therapy, however, have been disappointing. 4,5 Thus, we attempted to develop a strategy that would improve the performance of HSV-tk/GCV therapy when applied in combination.…”