Transform Switch Receptors (TSR) for armoring cell therapies

Novel fusion proteins that convert inhibitory signals in the tumor microenvironment into activating signals, enabling engineered immune cells to use immunosuppression as a source of functional support rather than dysfunction.

Background

The immunosuppressive tumor microenvironment is a major barrier to durable adoptive cell-therapy responses. Inhibitory ligands expressed by tumor, stromal, and immune cells can engage cognate receptors on therapeutic T cells, promoting dysfunction, reduced persistence, and diminished antitumor activity.

Technology

To overcome the immunosuppressive TME and to significantly improve the efficacy of adoptive cell therapy, Dr. Oda engineered Transform Switch Receptors (TSR). TSRs comprise an extracellular domain that recognizes an inhibitory TME ligand and an intracellular domain that delivers a stimulatory signal. When a TSR-expressing cell encounters a suppressive ligand in the tumor microenvironment, the receptor is designed to replace inhibitory signaling with a functional activation or costimulatory cue.

Benefits

  • Clinically informed modality: Builds on clinical experience with earlier-generation switch-receptor engineering while advancing new receptor configurations and ligand targets.

  • Modular, indication-specific design: Enables pairing of different inhibitory-ligand recognition domains with selected intracellular stimulatory domains to match tumor context and cell-product design.

  • TME-responsive enhancement: Designed to use immunosuppressive ligand engagement within the tumor microenvironment as a trigger for engineered-cell support.

  • Compatible with existing assets: Can be integrated with CAR-T, TCR-T, TIL, NK, CAR-NK, and iPSC-derived cell-therapy platforms.

  • Antigen-agnostic performance enhancer: Does not require expression of a single tumor-associated antigen as the TSR trigger, enabling use alongside diverse tumor-targeting strategies.

  • Flexible delivery and expression options: Amenable to viral or nanoparticle-based delivery approaches and potentially compatible with regulated or inducible expression systems.

Applications

  • Adoptive cell therapy for solid and hematological tumors

  • Amenable to in vivo gene approaches

  • Utility across iPSC, TIL, CAR-T, TCR-T, NK, and CAR-NK cell platforms