Recent progress in the research of suicide gene therapy for malignant glioma

Abstract

Malignant glioma, which is characterized by diffuse infiltration into the normal brain parenchyma, is the most aggressive primary brain tumor with dismal prognosis. Over the past 40 years, the median survival has only slightly improved. Therefore, new therapeutic modalities must be developed. In the 1990s, suicide gene therapy began attracting attention for the treatment of malignant glioma. Some clinical trials used a viral vector for suicide gene transduction; however, it was found that viral vectors cannot cover the large invaded area of glioma cells. Interest in this therapy was recently revived because some types of stem cells possess a tumor-tropic migratory capacity, which can be used as cellular delivery vehicles. Immortalized, clonal neural stem cell (NSC) line has been used for patients with recurrent high-grade glioma, which showed safety and efficacy. Embryonic and induced pluripotent stem cells may be considered as sources of NSC because NSC is difficult to harvest, and ethical issues have been raised. Mesenchymal stem cells are alternative candidates for cellular vehicle and are easily harvested from the bone marrow. In addition, a new type of nonlytic, amphotropic retroviral replicating vector encoding suicide gene has shown efficacy in patients with recurrent high-grade glioma in a clinical trial. This replicating viral capacity is another possible candidate as delivery vehicle to tackle gliomas. Herein, we review the concept of suicide gene therapy, as well as recent progress in preclinical and clinical studies in this field.

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Funding

This work was financially supported in part by grants from the Japan Society for the Promotion of Science (JSPS) (16K20026 to R.T., 17H04306 and 18K19622 to M.T.) and by the Research Center Network for the Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (18bm0204001h0006 to H.O.).

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Correspondence to Masahiro Toda.

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H.O. is a compensated scientific consultant of San Bio, Co., Ltd. and K Pharma Inc. The other authors declare no potential conflicts of interest.

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Tamura, R., Miyoshi, H., Yoshida, K. et al. Recent progress in the research of suicide gene therapy for malignant glioma. Neurosurg Rev 44, 29–49 (2021). https://doi.org/10.1007/s10143-019-01203-3

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Keywords

  • Suicide gene therapy
  • HSVtk
  • CD
  • GCV
  • 5FC
  • Neural stem cells