Genetically engineered macrophages (GEMs) for tumor immunotherapy

Background

Solid tumors have an immunosuppressive microenvironment that promotes proliferation of tumor cells while suppressing functions of cytotoxic immune cells. Anti-cancer therapies including immunotherapies are impaired by the suppressive tumor microenvironment. Developing strategies to overcome the immunosuppression can greatly enhance treatment options for solid tumors.

Macrophages and monocytes have the natural ability to home to inflammation and deeply infiltrate tumors. Methods that harness myeloid cells to deliver localized therapeutic payloads and orchestrate robust immune responses need to be explored.

Despite the potential of utilizing myeloid cells as delivery vehicles, current approaches face severe limitations. Conventional T-cell and natural killer cell therapies are frequently rendered ineffective by the highly immunosuppressive tumor microenvironment, which actively exhausts these lymphocytes. Additionally, attempting to modulate this hostile environment using systemic recombinant cytokines often causes severe, dose-limiting toxicity. A fundamental biological hurdle also prevents the effective use of myeloid cells: primary human macrophages possess a profound natural resistance to standard lentiviral transduction, preventing efficient genetic engineering using conventional vectors.

Technology

Using glioblastoma (GBM) as a model of solid tumors, Seattle Children’s researchers have demonstrated the utility of genetically engineered macrophages (GEMs) and monocytes for solid tumor immunotherapy.

This immunotherapy platform enables the robust genetic engineering of human primary macrophages (GEMs) and monocytes. The core technology utilizes a specialized lentiviral packaging system that overcomes the natural resistance of myeloid cells to lentiviral transduction. This system is modular and supports diverse therapeutic payloads, including Chimeric Antigen Receptors (CARs). The platform also integrates CRISPR/Cas9 genome editing to knock out immunosuppressive genes and expresses decoy receptors to neutralize tumor-induced signaling.

The engineered macrophages express factors that promote function of cytotoxic immune cells and factors that minimize the proliferation of tumor and suppressive cells. When implanted into a xenograft model of GBM, GEMs stably expressed the transgenes, persisted in the tumor and did not affect animal survival. Importantly, GEMs did not contribute to tumor growth and continued secreting factors that minimize microenvironment induced suppression. GEMs are ideal gene delivery vehicles that can function as a standalone immunotherapy or synergistically with existing immunotherapies.

Benefits

• Near complete transduction efficiency at low viral doses

• Effective tumor infiltration and persistence of GEMs

• Synergistic with existing cell therapies

• Rapid production of GEMs from patient monocyte population that is discarded during CAR T cell production

• Offers broad therapeutic applicability across oncology, viral infections, autoimmune disorders, and regenerative medicine

Applications

• GEMs as therapeutic gene delivery vehicles

• Solid tumor immunotherapy

• CAR macrophage cell therapy

• Adjuvant for cancer immunotherapy

• Targeted tumor cytokine delivery

Additional info

Issued patents in the US: 10,525,082 & 11,826,384