Microenvironment sensing macrophages

A novel engineered macrophage that delivers a therapeutic cargo by sensing the tumor microenvironment.

Background

Solid tumors harbor immunosuppressive microenvironments (ME) that promote tumor cell survival and proliferation while preventing the localization and function of infiltrating immune cells. Cell-based immunotherapies represent a rapidly advancing field in the treatment of complex, refractory diseases, including solid tumors. However, overcoming ME immunosuppression remains a challenge to developing successful immunotherapies. Additionally, delivery of potent therapeutic proteins to intended disease sites with temporal control remains a challenge.

Most conventional approaches rely on the constitutive expression of potent therapeutic cargo which could lead to severe systemic toxicity and dangerous off-target effects. On-target, off-tissue toxicity significantly narrows the therapeutic window, preventing safe systemic administration.

Technology

Crane and colleagues have developed an approach to overcome ME immunosuppression by utilizing macrophages as gene delivery vehicles. They engineered macrophages with a two-component lentiviral gene expression system that allows expression of a therapeutic cargo in immunosuppressive MEs. The ME is ‘sensed’ via endogenous signaling pathways triggered in the macrophages or via cell surface chimeric receptors on the macrophage that bind tumor ME specific soluble or receptor proteins. Upstream sensing activates a gene regulatory element and the therapeutic payload linked to it. Unlike constitutive expression models, microenvironment sensing macrophages can deliver therapeutic payloads in a controlled manner dictated by the status of the ME, achieving spatial and temporal control. This can overcome toxicity associated with non-specific expression of therapeutic genes, circumvent the need for tissue specific therapeutic delivery and enable therapeutic payload delivery to multiple sites.

Benefits

  • Tumor microenvironment specific payload delivery

  • Temporally and spatially controlled payload delivery

  • Synergistic with CAR T cell immunotherapy

  • Modular platform

Applications

  • Microenvironment sensing macrophages as therapeutic gene delivery vehicles

  • Targeted solid tumor therapy

  • Tumor microenvironment specific gene delivery