Abstract
Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.
Highlights
In what is known as cancer immunoediting, the immune system tries to eradicate the evolving tumor but, in doing so, shapes the immunogenicity of the tumor that may escape the immune control [1]
Tumors often decrease the expression of components required for antigen presentation (MHC) and/ or T cell activation as well as ligands for the NK cell-activating receptors in order to hide from the T and NK cells, respectively [1,2,3,4]
The loss of CD20 antigen following rituximab therapy has been observed for follicular lymphoma [27], B cell non-Hodgkin lymphoma (NHL) [28], and chronic lymphocytic leukemia (CLL) [29]
Summary
In what is known as cancer immunoediting, the immune system tries to eradicate the evolving tumor but, in doing so, shapes the immunogenicity of the tumor that may escape the immune control [1]. The following sections review the current targeted therapies and the evidences of relapses associated with antigen The most promising immunotherapeutic options for leukemia include targeted approaches such as chimeric antigen receptor (CAR) modified T cells (CAR-T cells) and antibody-based therapies that activate T and NK cells [11].
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