ALK a Novel Lymphoma-associated Tumor Antigen for Vaccination Strategies

Abstract

The discovery of Tumor Associated Antigens (TAAs) demonstrated that tumor cells can be specifically recognized by the immune system raising the hypothesis that tumors express antigens that Cytotoxic T Lymphocytes (CTLs) can potentially attack. The identification of immunogenic epitopes led to their use as targets to mediate the specific clearance of neoplastic cells by TAA targeting strategies such as vaccination strategies. One of the critical issues in the development of efficient vaccination protocols is the identification of the appropriate TAAs. The TAA should be effective as a "tumor rejection antigen" able to induce an immune response that will affect tumor growth. A distinct pathologic entity characterized by the expression of the Anaplastic Lymphoma Kinase (ALK) protein and named "ALKoma" has recently emerged within the heterogeneous group of CD30+ Anaplastic Large Cell Lymphoma (ALCL). ALK is a receptor tyrosine kinase whose expression is normally restricted to a few scattered cells in the nervous system. Its pathological expression in lymphoma cells is due to a chromosomal translocation that leads to the formation of an ALK-derived oncogenic fusion proteins. ALK fusion proteins ectopically over-expressed and constitutively activated in lymphoid cells play a key role in the neoplastic transformation by the aberrant phosphorilation of intracellular substrates that likely contributes to the molecular pathogenesis of ALCL. The high level of ALK expression in lymphoma cells and its direct role in lymphomagenesis, combined with the fact that normal ALK is expressed at low levels in the immune privileged nervous system, makes ALK an ideal lymphoma-specific target for immunotherapy of ALK+ALCL.