Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors
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Published on: July 16, 2018
Jordi Martinez-Quintanilla1, Deepak Bhere, Pedram Heidari
1Molecular Neurotherapy and Imaging Laboratory, Harvard Medical School, Boston, Massachusetts, USA; Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Therapeutically engineered stem cells (SC) are emerging as an effective tumor-targeted approach for different cancer types. However, the assessment of the long-term fate of therapeutic SC post-tumor treatment is critical if such promising therapies are to be translated into clinical practice. In this study, we have developed an efficient SC-based therapeutic strategy that simultaneously allows killing of tumor cells and assessment and eradication of SC after treatment of highly malignant glioblastoma multiforme (GBM). Mesenchymal stem cells (MSC) engineered to co-express the prodrug converting enzyme, herpes simplex virus thymidine kinase (HSV-TK) and a potent and secretable variant of tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) induced caspase-mediated GBM cell death and showed selective MSC sensitization to the prodrug ganciclovir (GCV). A significant decrease in tumor growth and a subsequent increase in survival were observed when mice bearing highly aggressive GBM were treated with MSC coexpressing S-TRAIL and HSV-TK. Furthermore, the systemic administration of GCV post-tumor treatment selectively eliminated therapeutic MSC expressing HSV-TK in vitro and in vivo, which was monitored in real time by positron emission-computed tomography imaging using 18F-FHBG, a substrate for HSV-TK. These findings demonstrate the development and validation of a novel therapeutic strategy that has implications in translating SC-based therapies in cancer patients.
Insights
Engineered stem cells (SC) target glioblastoma multiforme (GBM). A novel strategy uses SC to kill tumors and allows their elimination post-treatment, improving cancer therapy safety and efficacy.
Area of Science:
- Oncology
- Stem Cell Therapy
- Biotechnology
Background:
- Engineered stem cells (SC) show promise for targeted cancer therapy.
- Assessing the long-term fate of therapeutic SC post-treatment is crucial for clinical translation.
- Glioblastoma multiforme (GBM) is a highly malignant brain tumor requiring innovative therapeutic approaches.
Purpose of the Study:
- To develop an SC-based strategy for GBM treatment that enables tumor cell killing and post-treatment SC assessment and eradication.
- To evaluate the efficacy of engineered mesenchymal stem cells (MSC) co-expressing herpes simplex virus thymidine kinase (HSV-TK) and secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) in GBM models.
Main Methods:
- Mesenchymal stem cells (MSC) were engineered to co-express HSV-TK and S-TRAIL.
- The therapeutic efficacy was tested in mice bearing aggressive GBM xenografts.
- GCV administration was used to eliminate HSV-TK expressing MSC post-treatment.
- Positron emission-computed tomography (PET) imaging with 18F-FHBG monitored MSC elimination in real time.
Main Results:
- Engineered MSC induced caspase-mediated GBM cell death and sensitized MSC to ganciclovir (GCV).
- Treatment with MSC co-expressing S-TRAIL and HSV-TK significantly reduced tumor growth and increased survival in GBM-bearing mice.
- Systemic GCV administration selectively eliminated therapeutic MSC in vitro and in vivo.
- PET imaging confirmed real-time monitoring of MSC eradication.
Conclusions:
- A novel SC-based therapeutic strategy was developed and validated for GBM treatment.
- This approach allows for simultaneous tumor killing and controlled elimination of therapeutic SC.
- The findings have significant implications for the clinical translation of SC-based cancer therapies.
