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Generation of Multivirus-specific T Cells to Prevent/treat Viral Infections after Allogeneic Hematopoietic Stem Cell Transplant
Published on: May 27, 2011
Herpes simplex-1 virus thymidine kinase gene is unable to completely eliminate live, nonimmunogenic tumor cell
P T Golumbek1, F M Hamzeh, E M Jaffee
1Department of Medicine, Johns Hopkins University, Baltimore, MD 21205.
Abstract:
Recent experiments with genetically engineered tumors have generated renewed interest in active cellular immunotherapy as a cancer treatment modality. In order to consider the use of live tumor cells for immunotherapy in human cancer patients, it will be important to ensure that these cells do not themselves produce morbidity in the event the immune system fails to eliminate them. Toward this end, we have examined a strategy for eliminating genetically manipulated nonimmunogenic tumors in vivo. When B16F10 melanoma cells were transfected with the Herpes simplex virus 1 thymidine kinase (HSV-TK) gene, cells were rendered susceptible to killing by the nucleoside analogs acyclovir (ACV) and ganciclovir (GCV). B16-HSV-TK+ tumors established in C57BL6 mice were successfully "suicided" in vivo when GCV was administered by continuous infusion. However, late recurrences were observed even after 1 month of continuous GCV treatment. In vivo growth kinetics suggested that the recurrences resulted from a tiny number (< 20) of cells that had survived the GCV treatment. Interestingly, recurrent tumors were as sensitive to GCV as the parental B16-HSV-TK+ line. While these results demonstrate potential feasibility of the suicide gene strategy for active immunotherapy with live tumor cells, they also illustrate that approaches dependent on the intracellular generation of cell cycle-dependent toxins may fail to eliminate small numbers of cells that temporarily exit cell cycle or that are pharmacologically sequestered.
Insights
Genetically engineered tumor cells expressing the Herpes simplex virus thymidine kinase (HSV-TK) gene can be eliminated using ganciclovir (GCV). However, late tumor recurrences indicate this suicide gene therapy may not eradicate all cancer cells.
Area of Science:
- Oncology
- Cancer Gene Therapy
- Immunotherapy
Background:
- Active cellular immunotherapy shows promise for cancer treatment, but requires ensuring engineered tumor cells do not cause harm.
- A strategy is needed to eliminate genetically modified nonimmunogenic tumors in vivo.
- The Herpes simplex virus thymidine kinase (HSV-TK) gene can sensitize tumor cells to specific drugs.
Purpose of the Study:
- To evaluate the efficacy of a suicide gene strategy for eliminating genetically modified tumors in vivo.
- To determine if Herpes simplex virus 1 thymidine kinase (HSV-TK) gene-transfected tumors can be eradicated using nucleoside analogs.
- To assess the potential for late tumor recurrences after treatment.
Main Methods:
- B16F10 melanoma cells were transfected with the HSV-TK gene.
- Transfected tumors (B16-HSV-TK+) were established in C57BL6 mice.
- Continuous infusion of ganciclovir (GCV) was administered to treat established tumors.
Main Results:
- GCV treatment successfully eliminated established B16-HSV-TK+ tumors in vivo.
- Late tumor recurrences were observed even after one month of continuous GCV treatment.
- Recurrent tumors remained sensitive to GCV, suggesting survival of a small number of cells.
Conclusions:
- The suicide gene strategy using HSV-TK and GCV shows potential feasibility for active immunotherapy with live tumor cells.
- Approaches relying on cell cycle-dependent toxins may not eliminate all tumor cells due to cell cycle exit or sequestration.
- Further strategies are needed to ensure complete eradication of tumor cells in cancer immunotherapy.
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