Gene-Modified Lymphocytes: From Caution to Promise for Effective Cancer Immunotherapy

Abstract

Genetic modification of lymphocytes is a promising strategy to extend the application and improve the efficacy of adoptive T-cell therapy for patients with malignancy. The modification includes the forced expression of tumor-associated antigenspecific receptors in order to redirect the specificity of polyclonal lymphocytes. It can also help to express molecules responsible for enhancing their function, persistence in hosts or resistance against tumor-mediated immunosuppression. Recently, potential on-target adverse events were reported in some clinical trials of adoptive therapy that were utilizing T cells genetically modified to recognize antigens that are expressed in tumor cells and a subset of normal cells. Importantly, some of the target antigens in these reports had been targeted in other type of immunotherapies with limited toxicity. These adverse events highlight the need for us to be extremely careful in the use of adoptive T-cell therapy with gene-modified T cells as a cancer immunotherapy. On the other hand, they also encourage us to suggest the possibility that high-quality adoptive T-cell therapy may overcome the immuno logical tolerance that is often strengthened in the cancer-related microenvironment.