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Development of a TGFβ-IL-2/15 Switch Receptor for Use in Adoptive Cell Therapy
Carole Beck1, Nicholas Paul Casey1, Irene Persiconi1
1Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
Abstract:
Therapy employing T cells modified with chimeric antigen receptors (CARs) is effective in hematological malignancies but not yet in solid cancers. CAR T cell activity in solid tumors is limited by immunosuppressive factors, including transforming growth factor β (TGFβ). Here, we describe the development of a switch receptor (SwR), in which the extracellular domains of the TGFβ receptor are fused to the intracellular domains from the IL-2/15 receptor. We evaluated the SwR in tandem with two variants of a CAR that we have developed against STEAP1, a protein highly expressed in prostate cancer. The SwR-CAR T cell activity was assessed against a panel of STEAP1+/- prostate cancer cell lines with or without over-expression of TGFβ, or with added TGFβ, by use of flow cytometry cytokine and killing assays, Luminex cytokine profiling, cell counts, and flow cytometry phenotyping. The results showed that the SwR-CAR constructs improved the functionality of CAR T cells in TGFβ-rich environments, as measured by T cell proliferation and survival, cytokine response, and cytotoxicity. In assays with four repeated target-cell stimulations, the SwR-CAR T cells developed an activated effector memory phenotype with retained STEAP1-specific activity. In conclusion, the SwR confers CAR T cells with potent and durable in vitro functionality in TGFβ-rich environments. The SwR may be used as an add-on construct for CAR T cells or other forms of adoptive cell therapy.
Insights
Chimeric antigen receptor (CAR) T cells show promise for treating solid tumors by overcoming immunosuppressive factors like transforming growth factor beta (TGFβ) using a novel switch receptor (SwR). This SwR enhances CAR T cell functionality and durability in TGFβ-rich tumor environments.
Area of Science:
- Immunology
- Cancer Biology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T cell therapy is highly effective against hematological malignancies but faces challenges in solid tumors.
- The tumor microenvironment, particularly immunosuppressive factors like transforming growth factor beta (TGFβ), limits CAR T cell efficacy.
- STEAP1 is highly expressed in prostate cancer, making it a potential target for CAR T cell therapy.
Purpose of the Study:
- To develop and evaluate a novel switch receptor (SwR) designed to enhance CAR T cell activity in TGFβ-rich solid tumor environments.
- To assess the efficacy of SwR-engineered CAR T cells targeting STEAP1 in prostate cancer models.
Main Methods:
- Development of a switch receptor (SwR) by fusing TGFβ receptor extracellular domains with IL-2/15 receptor intracellular domains.
- Co-expression of SwR with anti-STEAP1 CAR constructs in T cells.
- In vitro assessment of SwR-CAR T cell function against STEAP1-positive and negative prostate cancer cell lines under varying TGFβ conditions using flow cytometry, cytokine assays, and cytotoxicity assays.
Main Results:
- SwR-CAR T cells demonstrated improved proliferation, survival, cytokine production, and cytotoxicity in the presence of TGFβ.
- Repeated stimulations resulted in an activated effector memory phenotype with sustained STEAP1-specific activity.
- The SwR conferred potent and durable in vitro functionality to CAR T cells in immunosuppressive, TGFβ-rich conditions.
Conclusions:
- The developed switch receptor (SwR) effectively enhances CAR T cell functionality in TGFβ-rich environments, addressing a key limitation in solid tumor therapy.
- SwR-modified CAR T cells show potential for durable anti-tumor activity against STEAP1-expressing prostate cancers.
- The SwR represents a promising add-on strategy for CAR T cells and other adoptive cell therapies to overcome tumor-induced immunosuppression.
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