Harnessing the Power of CT-0508: Unleashing an Anti-HER2 Proinflammatory Tumor Microenvironment

T cell immunotherapy has made significant strides in cancer treatment, yet metastatic solid tumors continue to pose significant challenges. Within the tumor microenvironment (TME), macrophages often exist as immunosuppressive tumor-associated macrophages (TAMs), contributing to disease progression. Traditional macrophage-based therapies aim to decrease TAM presence or enhance their phagocytic capabilities.

A novel approach involves the use of chimeric antigen receptor (CAR) macrophages (CAR-M), genetically engineered cells that can be produced using a specific adenoviral vector due to the resistance of human macrophages to other gene transfer methods. The CAR-M's primary function is through phagocytosis, and early studies have shown that a single dose of anti-HER2 CAR-M can significantly improve survival in xenograft models.

The CAR-M product CT-0508 has been developed to adopt a proinflammatory and antitumor M1 phenotype. It has been shown to maintain this phenotype even when faced with immunosuppressive conditions in vitro, indicating its resilience. A new xenografted human TME model was created to demonstrate that CT-0508 retains its phenotype within the human TME and can activate it, leading to the generation of an activated human dendritic cell signature.

CT-0508 has also been observed to shift nearby macrophages toward a proinflammatory phenotype, stimulate activation and maturation markers on dendritic cells, and attract both resting and activated T cells in chemotaxis assays. Moreover, it has demonstrated superior antigen presentation capabilities compared to control human macrophages.

These findings suggest that CT-0508 not only has direct antitumor effects but can also activate the TME of solid cancers and foster a proinflammatory environment. The safety and potential of CT-0508 will be further explored in an upcoming phase I clinical trial, marking a new direction in CAR macrophage therapy for cancer treatment.