Discussion
glioma, allogeneic stem cell-mediated suicide, tumor
ADENOVIRUS, TUMOR, RECURRENCE, DISEASE, COMPLICATION, GLIOMA
The present first-in-human phase I clinical trial demonstrated several significant findings regarding the use of a novel allogeneic stem cell-mediated suicide gene therapy protocol in patients with recurrent GBM. The suicide gene therapy protocol, including stereotactic injection of allogeneic ADSC gene delivery vehicles was safe in patients with recurrent GBM and no early- or late-onset complication was observed over the study period. Additionally, among 12 patients, 8 showed partial response and others had stable disease as the best response. Volumetric analysis also revealed significant reductions in both CET and FLAIR volumes that were durable for 12 months postoperatively. Further, specific changes in cytokine profile and peripheral blood cells were noted following this gene therapy protocol.This study found that the present novel suicide gene therapy protocol using allogeneic ADSC gene vehicles carrying HSV-TK gene was safe without any DLT in patients with recurrent GBM. Prior to this investigation, initial early-phase clinical trials and also larger investigations had demonstrated the safety profile of suicide gene therapy using viral vectors, such as retrovirus and adenovirus in patients with GBM [Furthermore, this novel protocol showed significant potential for improving both PFS and OS in patients with recurrent GBM. According to prior findings, patients with recurrent glioma have a median OS and PFS of 4.93 (95% CI 4.37–5.48) and 1.80 months (95% CI 1.56–2.03), respectively [In addition, based on MR images, in comparison with the baseline, both CET and FLAIR volumes showed a substantial reduction at 6- and 12-months postoperatively. This long-term response observed in patients with recurrent GBM might be attributable to the cytotoxic effects of suicide gene therapy using ADSC gene vehicles similar to preclinical results indicating the role of “bystander effect” in this therapeutic strategy using ADSCs [Immunological profile, including both peripheral blood cells and cytokines showed marked changes over the study period. Absolute lymphocyte, CD4Despite many strengths, the present investigations had some limitations. First, given the main aim of this study, which was safety evaluation and MTD determination, it was performed with one single arm without any control group. Although compared with prior evidence, the present gene therapy protocol led to significant results in terms of both clinical and radiological response in recurrent GBM, future phase II and III clinical trials with larger sample sizes and control arms are highly demanded to allow for comparison between this protocol and standard therapy. Second, all the procedures as well as perioperative care was performed in one center, which might have affected the survival and clinical outcome of the patients. Thus, future multicenter investigations should validate these findings. Third, due mainly to ethical considerations, it was not applicable to perform a second biopsy after the stereotactic injection. Moreover, patients who died in this study had decline the autopsy. Accordingly, histopathological analysis of changes in the tumor microenvironment could not be performed. Hence, future preclinical or clinical evidence in this regard is required to clarify the mechanisms underlying observed radiological response in this study. Fourth, this clinical trial only included patients with recurrent GBM, who did not undergo any treatment modality, such as surgery or chemoradiotherapy for their recurrence. Therefore, it is unknown whether the combination of the present cell-based suicide gene therapy protocol and other treatment modalities leads to a better clinical response. Further, future investigations should evaluate the effects of this gene therapy on outcomes of patients with newly diagnosed GBM.