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Pharmacologic suppression of target cell recognition by engineered T cells expressing chimeric T-cell receptors
L Alvarez-Vallina1, R Yañez, B Blanco
1Department of Immunology, Hospital Universitario Clínica Puerta de Hierro, Madrid, Spain. Luis.Alvarez@inmu.cph.es
Abstract:
Adoptive therapy with autologous T cells expressing chimeric T-cell receptors (chTCRs) is of potential interest for the treatment of malignancy. To limit possible T-cell-mediated damage to normal tissues that weakly express the targeted tumor antigen (Ag), we have tested a strategy for the suppression of target cell recognition by engineered T cells. Jurkat T cells were transduced with an anti-hapten chTCR tinder the control of a tetracycline-suppressible promoter and were shown to respond to Ag-positive (hapten-coated) but not to Ag-negative target cells. The engineered T cells were then reacted with hapten-coated target cells at different effector to target cell ratios before and after exposure to tetracycline. When the engineered T cells were treated with tetracycline, expression of the chTCR was greatly decreased and recognition of the hapten-coated target cells was completely suppressed. Tetracycline-mediated suppression of target cell recognition by engineered T cells may be a useful strategy to limit the toxicity of the approach to cancer gene therapy.
Insights
Engineered T cells for cancer therapy can be controlled using tetracycline. This method suppresses T-cell recognition of target cells, potentially reducing side effects in adoptive T-cell therapy.
Area of Science:
- Immunology
- Cancer Gene Therapy
- Cellular Therapy
Background:
- Adoptive T-cell therapy using chimeric T-cell receptors (chTCRs) shows promise for treating malignancies.
- A key challenge is mitigating T-cell-mediated damage to normal tissues expressing low levels of tumor antigens.
- Controlling the activity of engineered T cells is crucial for enhancing safety.
Purpose of the Study:
- To investigate a strategy for suppressing target cell recognition by engineered T cells.
- To evaluate the efficacy of tetracycline-inducible systems in controlling chTCR-expressing T cells.
- To assess the potential of this approach for limiting on-target, off-tumor toxicity in cancer gene therapy.
Main Methods:
- Jurkat T cells were engineered to express an anti-hapten chTCR under a tetracycline-suppressible promoter.
- Engineered T cells were tested for recognition of hapten-coated (antigen-positive) and uncoated (antigen-negative) target cells.
- The effect of tetracycline treatment on chTCR expression and target cell recognition was analyzed at various effector-to-target cell ratios.
Main Results:
- Engineered T cells specifically recognized hapten-coated target cells.
- Tetracycline treatment significantly reduced chTCR expression in the engineered T cells.
- Target cell recognition by the engineered T cells was completely suppressed upon tetracycline administration.
Conclusions:
- Tetracycline-mediated suppression of chTCR activity offers a controllable method for regulating engineered T cells.
- This inducible suppression strategy may be valuable for minimizing toxicity associated with adoptive T-cell therapy.
- The findings support the development of safer and more targeted cancer gene therapies.