Combination Immunotherapy Targeting Melanoma

The purpose of this study is to assess the feasibility, safety and efficacy of combination immunotherapy based on CAR T cells, cytotoxic T lymphocytes (CTLs), and dendritic cell (DC) vaccines modified with GM-CSF and B7-2 (CD86) against melanoma, which targets CAR T specific surface antigens such as GD2, CTL specific antigens such as MAGE-A4, gp100 and a pool of melanoma specific antigens presented by the DCs. Another goal of the study is to learn more about the function and persistence of the CAR T cells and antigen-specific immune effectors in patients.

Melanoma, known for having the highest mutation burden among solid tumors, has seen a steady rise in incidence over recent years. Early-stage melanoma can often be treated by surgery. As the tumor invades deeper and cancer cells metastasize, the difficulty of radical surgery increases. Although targeted therapies have significantly improved survival rates for patients with advanced melanoma, the potential for drug resistance remains a significant challenge. In this context, immunotherapy has become a new area of exploration.Therapies such as chimeric antigen receptor (CAR) T cell therapy, cytotoxic T lymphocyte (CTL) therapy, and dendritic cell vaccines have demonstrated promising clinical outcomes across various tumor types. Moreover, clinical trials exploring the application of these immunotherapies for treating melanoma are advancing steadily. Consequently, this study aims to explore a novel approach to melanoma treatment by integrating these three distinct forms of immunotherapy. CAR T cells are a specialized type of T cells engineered to recognize and eliminate tumor cells by targeting specific surface antigens. The selection of the appropriate target antigens is crucial for the efficacy of CAR T cell therapy. Recent research has identified several promising targets for melanoma treatment, including GD2, CD70, and CSPG4. The choice of target may depend on individual patient characteristics. Among these, GD2 is expressed on the surface of a majority of melanoma cells while being minimally present in normal tissues, making it a favorable target in melanoma treatment. CTL therapy involves stimulating effector T cells with antigen-presenting cells targeting cancer-specific antigens. In order to enhance the tumor-specific immune response, these activated antigen-presenting cells are used to generate highly specific T cells. Studies have identified several melanoma-associated antigens, such as gp100, tyrosinase, Melan-A, MAGE-A1, MAGE-A4, and NY-ESO-1. gp100 and MAGE-A4 are expressed in a significant proportion of melanoma cells and are closely linked to the development and progression of the disease. Furthermore, aberrant expression of gp100 may be implicated in the malignant transformation of melanocytes. The dendritic cell (DC) vaccine leverages DC to activate T cells that specifically recognize target antigens, with the goal of preventing cancer recurrence and controlling tumor growth. Research has shown that DC vaccines modified with immune modulators such as GM-CSF and B7-2 (CD86) hold potential for melanoma treatment. GM-CSF plays a critical role by upregulating the expression of Bcl-xL in DC cells and reducing their sensitivity to immunosuppressive cytokines, thereby ensuring the optimal function of DCs. B7-2 serves as a vital ligand for T cell activation. By modifying DCs with B7-2, the interaction between DCs and T cells is enhanced, and promoting T cell activation, which collectively contribute to anti-tumor response. The primary objective of this study is to evaluate the feasibility, safety, and efficacy of a combination therapy that integrates CAR T cells, CTLs, and DC vaccines modified with GM-CSF and B7-2 (CD86) for the treatment of melanoma. Additionally, the study seeks to gain further insights into the function and persistence of CAR T cells and antigen-specific immune effector s in patients.