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Developing and characterizing a two-layered safety switch for cell therapies
Filippo Rossignoli1,2, Danielle Hoffman1,2, Emaan Atif1,2
1Center for Stem Cell and Translational Immunotherapy (CSTI), Harvard Medical School, Boston, MA, USA.
Cancer Biology & Therapy
|July 13, 2023
Summary
Engineered cells for therapy can be made safer with a novel double suicide system. This system uses two kill switches, RapaCasp9 and HSV-TK, to control cell elimination and ensure therapeutic safety.
Area of Science:
- Biotechnology
- Cellular Therapy
- Cancer Research
Background:
- Gene-edited cell therapies offer therapeutic potential but raise safety concerns due to cell persistence and toxicity.
- Existing one-dimensional suicide systems lack comprehensive control over therapeutic cell elimination.
Purpose of the Study:
- To engineer a robust two-layered suicide system for enhanced safety and controlled elimination of therapeutic engineered cells.
- To validate the efficacy and reliability of a dual-kill switch system in various cell types and preclinical models.
Main Methods:
- Engineered therapeutic cells to express two distinct suicide genes: RapaCasp9 and HSV-TK.
- Activated suicide systems using specific drugs: Rapamycin for RapaCasp9 and Ganciclovir for HSV-TK.
- Assessed apoptosis induction, cell eradication in vitro and in vivo (subcutaneous and orthotopic models), and sequential activation efficacy.
Main Results:
- Both RapaCasp9 and HSV-TK demonstrated preserved function and induced apoptosis at distinct time points (24h and 48h) post-activation without observed toxicity.
- Significant eradication of therapeutic cells was achieved in vivo across different models.
- Sequential activation of both suicide switches provided improved cell killing, establishing a failsafe mechanism.
Conclusions:
- The developed double suicide system offers a reliable and effective method for controlling engineered cell populations.
- This failsafe mechanism enhances the safety profile of cell-based therapies, applicable across diverse cell types and anatomical locations.
