用于过继细胞治疗的 TGF-β-IL-2/15 转换受体开发

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 (TGF ).

Here, we describe the development of a switch receptor (SwR), in which the extracellular domains of the TGF 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 TGF , or with added TGF , 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 TGF -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 TGF -rich environments. The SwR may be used as an add-on construct for CAR T cells or other forms of adoptive cell therapy.