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Killer Artificial Antigen Presenting Cells (KaAPC) for Efficient In Vitro Depletion of Human Antigen-specific T Cells
Published on: August 11, 2014
Pharmacologically regulated Fas-mediated death of adoptively transferred T cells in a nonhuman primate model
Carolina Berger1, C Anthony Blau, Meei-Li Huang
1Department of Medicine, Klinikum Grosshadern, University of Munich, Germany.
Abstract:
Conditional suicide genes derived from pathogens have been developed to confer drug sensitivity and enhance safety of cell therapy, but this approach is limited by immune responses to the transgene product. We examined a strategy to regulate survival of transferred cells based on induction of apoptosis through oligomerization of a modified human Fas receptor by a bivalent drug (AP1903). Three macaques (Macaca nemestrina) received autologous T cells retrovirally engineered to express a Fas suicide-construct (LV'VFas). High levels of transduced cells were present in blood following cell transfer, but LV'VFas(+) cells declined rapidly after AP1903 administration. A small fraction of LV'VFas(+) cells resisted elimination by AP1903, in part due to insufficient levels of transgene expression in resting T cells, because reactivation of these cells in vitro enhanced sensitivity to AP1903. An immune response to the transgene product was observed, but epitope mapping indicated the response was directed to discrete components of human LV'VFas that were variant with the corresponding macaque sequences. These data demonstrate that chemically induced dimerization can be used to regulate survival of adoptively transferred T cells in vivo.
Insights
Chemically induced dimerization offers a novel method to control cell therapy survival. This approach uses a modified Fas receptor and a drug to eliminate engineered T cells, mitigating immune responses and enhancing safety.
Area of Science:
- Cell Therapy
- Immunology
- Molecular Biology
Background:
- Conditional suicide genes enhance cell therapy safety but can trigger immune responses.
- Existing methods face limitations due to immunogenicity of transgene products.
Purpose of the Study:
- To investigate a novel strategy for regulating the survival of adoptively transferred T cells.
- To utilize chemically induced dimerization of a modified human Fas receptor for controlled apoptosis induction.
Main Methods:
- Engineered autologous T cells from macaques (Macaca nemestrina) with a Fas suicide-construct (LV'VFas).
- Administered a bivalent drug (AP1903) to induce oligomerization and apoptosis of engineered cells.
- Assessed cell survival, transgene expression, and immune responses in vivo and in vitro.
Main Results:
- LV'VFas(+) T cells declined rapidly after AP1903 administration.
- A fraction of cells resisted elimination, partly due to low transgene expression in resting T cells.
- Immune responses were observed, directed at variant human Fas components, not conserved macaque sequences.
Conclusions:
- Chemically induced dimerization effectively regulates the survival of adoptively transferred T cells in vivo.
- This method offers a potential strategy to enhance the safety of cell therapies by controlling engineered cell persistence.
- Understanding epitope mapping is crucial for minimizing immune responses to xenogeneic transgenes.
