NG2 and DLL3 CAR-T Cells Targeting Melanoma

Melanoma, known for having the highest mutation burden among solid tumors, is in a steady rise in incidence over recent years. Early-stage melanoma can be treated by surgery. As the tumor invades deeper and cancer cells metastasize, the difficulty of radical surgery increases, and melanoma is highly resistant to conventional chemotherapy and radiation therapy. In this context, immunotherapy has become a new area of exploration. NG2 (chondroitin sulfate protein polysaccharide 4) is a cell surface type I transmembrane proteoglycan with substantial advantages as a potential therapeutic target for melanoma. On one hand, it exhibits strong targeting specificity, showing high expression in melanoma cells and in tumor angiogenesis-related blood vessels while maintaining low expression in normal tissues. This enables its targeted delivery to tumor sites, reducing damage to healthy tissues and minimizing side effects. On the other hand, NG2 involves multiple mechanisms: it not only participates in melanoma cell proliferation and survival but also plays a crucial role in tumor angiogenesis. Targeting NG2 may simultaneously inhibit both tumor cell growth and angiogenesis. Additionally, NG2 demonstrates prognostic value, as studies show its high expression correlates with better disease-free survival (DFS) in melanoma patients. This makes it a prognostic marker that helps assess disease progression and prognosis, providing valuable insights for treatment regimen formulation. Another potential therapeutic target, delta-like ligand 3 (DLL3), demonstrates three key advantages: first, it exhibits high targeting specificity - showing low expression in normal tissues but high expression in melanoma cells. This enables precision targeting by related drugs (such as antibody conjugates ADCs and CAR-T) to effectively attack tumors while minimizing damage to healthy tissues and reducing toxic side effects. Second, it restoring Notch signaling to inhibit tumor cell growth while blocking angiogenesis and epithelial mesenchymal transition (EMT), thereby suppressing cancer progression from both cellular and microenvironmental dimensions. Third, it shows broad clinical prospects, serving as a prognostic marker to guide personalized treatment and providing new therapeutic options for DLL3-positive patients with poor response to PD-1 inhibitors, potentially breaking through the treatment bottleneck in advanced melanoma. The purpose of this clinical study is to assess the feasibility, safety and efficacy of the combinational NG2 and DLL3 CAR T cell immunotherapy in patients who have melanoma in relapsed state or late stage.