Gene Therapy for Glioblastoma in Adult Patients: Safety and Efficacy Evaluation of an In Situ Injection of Recombinant Retroviruses Producing Cells Carrying the Thymidine Kinase Gene of the Herpes Simplex Type 1 Virus, to be Followed with the Administration of Ganciclovir. Laboratoire Immunologie B, Hôpital Pitié-Salpêtrière, Paris Cedex, France

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Abstract
This protocol aims at defining the safety and efficacy of an anticancer treatment for patients with a glioblastoma relapse. This treatment, sequentially administered to two different groups of patients in two escalating doses, consists in surgical injections within the surgical margin of the tumoral cavity of cells that produce recombinant retroviruses, followed with the administration of ganciclovir (GCV). This therapy is based on the introduction of a suicide gene within tumoral cells: the thymidine kinase gene from the herpes simplex type 1 (HSV1-TK) virus. This HSV1-TK gene sensitizes the cells to the toxicity of GCV, a drug without toxicity for normal cells, but one that kills those generating the HSV1-TK enzyme. Such destruction is restricted to dividing cells. Introducing the gene within tumoral cells is achieved through in situ injections of murine fibroblastic cells modified by genetic engineering (M11 cells). The latter constantly produce recombinant retroviruses containing the HSV1-TK gene. Such retroviruses can only express their genes when the cells they have infected are in cycle. This is the reason why, once the M11 cells have been injected inside the tumor, the HSV1-TK gene is only expressed by tumoral cells and therefore, they, alone, are killed by GCV. Inversely, the normal cells of the surrounding brain tissue can neither be transduced nor sensitized to GCV toxicity in as much as they have no mitotic activity. Moreover, tumoral cells that do not express the gene, but are in the immediate vicinity of transduced ones, are also killed (“metabolic cooperation” effect, also restricted to dividing cells). Thus, it is not necessary for all tumoral cells to express the HSV1 gene in order for them to all be killed. The efficacy of the above therapeutic approach has been evidenced with animals in the treatment of brain tumors, of colic adenocarcinoma hepatic metastases and of malignant melanoma. A therapeutic trial on recurrent brain tumors or metastases has begun in the USA, using a similar approach. We propose a stage I—II clinical trial for the treatment of glioblastoma in adults. The patients to be included in this study have to show a relapsing glioblastoma. In spite of a renewed surgical intervention—the sole possible therapeutic action at this stage, most of the time—the median of survival for such patients does not exceed seven months. M11 cells are injected in situ in the wall of the tumoral cavity, after removal is judged macroscopically complete. The injected M11 cell-dose is adjusted to fit the size of the relapsing tumor, a size quantified by means of magnetic resonance (MRI) during the pre-selection period. Two dose-levels are planned with, at the second level, two extra injections on the 7th and 14th days, using an Ommaya reservoir. The injection of M11 cells is to be followed with a 10mg/kg/day i-v administration of GCV. For each dose-level, the safety and efficacy of the treatment are assessed using Fleming's sequential plan.