Anti-MAGE-A4 CAR-NK cell therapy for the treatment of Melanoma

Abstract

Therapy with T-CAR cells against hematological neoplasm antigens, such as CAR-T anti CD19, has shown excellent remission rates. However, this type of CAR-T cell therapy is limited by the availability of tumor-specific surface antigens, sparing normal cells. There is a rich diversity of intracellularly expressed tumor protein antigens that current and conventional CAR-T cells are unable to target. In addition, adoptively transferred T cells often experience exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. In this sense, the development of alternatives to the use of genetically modified T cells is of great importance. NK (natural killer) cells due to their distinct MHC-independent mechanisms of action, intrinsic ability to recognize tumor cells through their native receptors (making tumor cell evasion less likely by negatively reducing the CAR target antigen), rapid cytokine production and cytotoxic granules after activation, low potential to cause GVHD, reduced probability of causing CRS and can be used as a ready-to-use product is becoming a source of resources for cell therapy with CAR. The Mage A4 intracellular antigen is highly expressed in a variety of cancers of diverse histological origins and has a low level of expression in normal tissues. Due to its relatively high tumor specificity, it represents an attractive target for specific and adoptive active cancer immunotherapies. The present project will use a CAR vector that will identify the Mage A4 antigen complexed with HLA0201 or HLA0206 (called TCR like CAR). TCR like CAR-T means that instead of isolating and using the T cell receptor, the CAR construct was based on a human antibody that recognizes the MAGEA4 complex in complex with HLA0201/0206. This construction was developed by one of our international collaborators (Prof. Shiku, Mie University). The therapeutic efficacy of TCR like CAR-T Mage A4 has already been demonstrated by the Japanese group and in this project, our main objective is to demonstrate the therapeutic efficiency of this innovative vector in our already established NK-CAR cell platform. This project will open therapeutic pathways that combine the efficiency of killing NK cells with the recognition of diversified targets of TCR-likes, with the advantage of having superior affinity to natural TCRs. (AU)