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Efficacy of HSV-TK/GCV system suicide gene therapy using SHED expressing modified HSV-TK against lung cancer brain
Tomoya Oishi1, Masahiko Ito2, Shinichiro Koizumi1
1Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Abstract:
Lung cancer is one of the most common cancers, and the number of patients with intracranial metastases is increasing. Previously, we developed an enzyme prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system using various mesenchymal stem cells to induce apoptosis in malignant gliomas through bystander killing effects. Here, we describe stem cells from human exfoliated deciduous teeth (SHED) as gene vehicles of the TK/GCV system against a brain metastasis model of non-small cell lung cancer (NSCLC). We introduced the A168H mutant TK (TKA168H) into SHED to establish the therapeutic cells because of the latent toxicity of wild type. SHED expressing TKA168H (SHED-TK) exhibited chemotaxis to the conditioned medium of NSCLC and migrated toward implanted NSCLC in vivo. SHED-TK demonstrated a strong bystander effect in vitro and in vivo and completely eradicated H1299 NSCLC in the brain. SHED-TK cells implanted intratumorally followed by GCV administration significantly suppressed the growth of H1299 and improved survival time. These results indicate that the TKA168H variant is suitable for establishing therapeutic cells and that intratumoral injection of SHED-TK followed by GCV administration may be a useful strategy for therapeutic approaches.
Insights
Stem cells from human exfoliated deciduous teeth (SHED) engineered with a mutant herpes simplex virus thymidine kinase (HSV-TK) gene effectively target and eliminate non-small cell lung cancer brain metastases in preclinical models.
Area of Science:
- Oncology
- Gene Therapy
- Stem Cell Biology
Background:
- Intracranial metastases from non-small cell lung cancer (NSCLC) pose a significant clinical challenge.
- Enzyme prodrug suicide gene therapy, utilizing the herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) system, has shown promise in treating brain tumors via bystander effects.
Purpose of the Study:
- To evaluate stem cells from human exfoliated deciduous teeth (SHED) engineered with a mutant TK gene (TKA168H) as a novel gene therapy vector for NSCLC brain metastases.
- To assess the efficacy and safety of SHED-TK cells combined with GCV in a preclinical model of NSCLC brain metastasis.
Main Methods:
- Engineered SHED with a latent toxic-free mutant HSV-TK (TKA168H) to create SHED-TK therapeutic cells.
- Assessed SHED-TK cell chemotaxis towards NSCLC conditioned medium and *in vivo* migration towards implanted tumors.
- Evaluated the *in vitro* and *in vivo* bystander killing effects of SHED-TK cells on NSCLC cells.
- Administered GCV following intratumoral implantation of SHED-TK cells in a brain metastasis model.
Main Results:
- SHED-TK cells demonstrated chemotaxis and migration towards NSCLC cells both *in vitro* and *in vivo*.
- SHED-TK cells exhibited potent bystander killing effects, leading to complete eradication of H1299 NSCLC in the brain.
- Intratumoral SHED-TK cell implantation followed by GCV administration significantly inhibited tumor growth and improved survival time.
Conclusions:
- The TKA168H variant is a suitable genetic modification for establishing effective therapeutic cells.
- Intratumoral delivery of SHED-TK cells combined with GCV represents a promising therapeutic strategy for treating NSCLC brain metastases.
