Chimeric Transforming Growth Factor Beta Receptor (CTBR)

The Chimeric Transforming Growth Factor Beta Receptor (CTBR) is a synthetic protein module engineered into immune cells, such as CAR-T or TCR-T cells, to overcome the immunosuppressive effects of the tumor microenvironment (TME). In many solid tumors, high levels of Transforming Growth Factor Beta (TGF-β) typically signal through endogenous receptors to inhibit T-cell proliferation and induce exhaustion (Narayan et al., 2022, Nature Medicine). The CTBR module addresses this by fusing the extracellular binding domain of the TGF-β receptor (usually TGFBR2) to an intracellular signaling domain from a stimulatory receptor, such as the IL-7 receptor, 4-1BB, or IL-12 receptor (Chang et al., 2023, Nature Communications). This switch receptor architecture allows the engineered cell to interpret the inhibitory TGF-β signal as a potent activation or survival signal, thereby enhancing anti-tumor efficacy and persistence. Alternatively, a dominant-negative version (dnTGFβRII) may be used to sequester TGF-β and prevent endogenous inhibitory signaling without providing a positive stimulus (Kloss et al., 2018, Molecular Therapy). These modules are currently being evaluated in clinical trials for various solid malignancies, including prostate and pancreatic cancers, where TGF-β-mediated immune evasion is a significant barrier to therapy.

Other names

TGF-beta chimeric switch receptorTGFβ-CSRTGFβ-IL7R switch receptorDominant-negative TGF-beta receptor IIdnTGFβRIITGF-beta-4-1BB switch receptor

Converts immunosuppressive TGF-beta signaling into immunostimulatory signaling or blocks endogenous TGF-beta signaling to prevent T-cell exhaustion.