Targeting GD2 with AUTO6NG: Overcoming Immunosuppression in Solid Tumors

Immune-checkpoint therapies have shown significant clinical success, with approvals across various cancer types. However, they face challenges in eliciting lasting responses in some solid tumors. The complexity of immunosuppressive mechanisms in the tumor microenvironment (TME) is a key factor hindering progress. CAR-T cell therapies have been notably effective in blood cancers but have not yet achieved similar success in solid tumors due to the suppressive TME.

In our research, we utilized tissue cytometry to analyze 30 markers across different TME components from patients with solid tumors expressing the antigen GD2. This comprehensive approach aimed to understand the interactions between tumor cells, T cells, dendritic cells, macrophages, MDSCs, CAFs, and endothelial cells within the TME. Machine learning was employed to uncover potential therapeutic targets within the TME of these tumors.

We developed CAR-T cells targeting GD2, an antigen found in multiple solid tumor types, and enhanced their functionality with a CCR module for improved persistence, a dnTGFβ to counteract TGFβ inhibitory signals, and other modules to boost their activity. These multi-module CAR-T cells exhibited robust in vitro anti-tumor activity and enhanced tumor infiltration and efficacy in vivo in mouse models.

Our study indicates that CAR-T cell therapies targeting GD2 offer a promising new strategy for treating a range of solid tumors. The findings were presented by Margarida Neves et al. at the American Association for Cancer Research Annual Meeting in 2020.