Development of Nectin4/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for malignant solid tumors

Area of Science:

• Oncology
• Immunotherapy
• Cell Therapy

Background:

• Chimeric antigen receptor T (CAR-T) cell therapy is effective for blood cancers but faces challenges in solid tumors due to the immunosuppressive tumor microenvironment.
• Identifying novel targets is crucial for advancing CAR-T therapy against solid malignancies.

Purpose of the Study:

• To investigate Nectin4 and Fibroblast Activation Protein (FAP) as potential targets for CAR-T cell therapy in solid tumors.
• To engineer and evaluate novel fourth-generation Nectin4-targeted and FAP-targeted CAR-T cells.

Main Methods:

• Immunohistochemistry was used to assess Nectin4 and FAP expression in various solid tumors.
• Fourth-generation Nectin4-targeted (Nectin4-7.19 CAR-T) and FAP-targeted (FAP-12 CAR-T) cells were engineered.
• In vitro and in vivo studies were conducted in mouse models of metastatic colorectal and lung cancer.

Main Results:

• Nectin4 was overexpressed on primary and metastatic solid tumors, while FAP was found on cancer-associated fibroblasts.
• Nectin4-7.19 CAR-T cells demonstrated enhanced proliferation, migration, and cytotoxicity compared to second-generation CAR-T cells.
• Nectin4-7.19 CAR-T and FAP-12 CAR-T cells eradicated tumors and improved survival in preclinical models, showing a synergistic effect.

Conclusions:

• Nectin4 and FAP are promising targets for developing safe and effective CAR-T cell therapies for solid tumors.
• Nectin4-7.19 CAR-T cells exhibit significant therapeutic potential and synergistic activity with FAP-12 CAR-T cells.