Dual Costimulatory Receptors (DCR) for adoptive cell therapy

Novel hybrid receptors that enhance the efficacy of adoptive cell therapies by driving local antigen presentation and epitope spreading

Background

Adoptive cell therapies can be limited by tumor heterogeneity, antigen loss, and an insufficient endogenous immune response. Even when engineered cells kill antigen-positive tumor cells, untreated tumor subclones may escape.

Technology

To address current challenges, Dr. Oda has engineered modular hybrid receptors called Dual Costimulatory Receptors (DCR). DCRs combine a stimulatory extracellular domain—such as CD40L, OX40L, or 4-1BBL—with a distinct intracellular costimulatory domain. DCR-expressing therapeutic cells engage TNF-family receptors on dendritic cells, macrophages, B cells, and other local immune cells, promoting antigen presentation and endogenous immune activation while supporting engineered-cell persistence and antitumor function. By recruiting endogenous immunity, DCRs are designed to extend antitumor activity beyond direct recognition of a single target antigen, addressing tumor heterogeneity through mechanisms such as dendritic-cell activation, macrophage phagocytosis, and endogenous T-cell epitope spreading.

Benefits

  • Addresses tumor heterogeneity: Designed to recruit endogenous APC and T-cell responses against tumor antigens beyond the engineered cell’s primary recognition target.

  • Potential for epitope spreading: In vitro and in vivo studies show dendritic-cell activation, macrophage phagocytosis, and activation of endogenous T cells, consistent with induction of broader antitumor immunity.

  • Modular receptor toolbox: Includes extracellular domains such as CD40L, OX40L, and 4-1BBL with multiple intracellular costimulatory-domain options.

  • Compatible with multiple cell modalities: Applicable to CAR-T, TCR-T, TIL, NK, CAR-NK, iPSC-derived, macrophage, and dendritic-cell platforms.

  • Complementary to existing targeting assets: Designed to layer onto an antigen-directed cell therapy, rather than requiring replacement of its CAR, TCR, or primary tumor-recognition strategy.

  • Engineering flexibility: Amenable to viral or nanoparticle-based delivery and potentially compatible with regulated or inducible expression strategies.

Applications

  • Solid tumor cell therapy

  • Hematological cancer immunotherapy

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

  • Amenable to in vivo approaches