Epigenetic Strategies to Optimize CAR-T Therapy

Abstract

Chimeric antigen receptor T (CAR-T) cells that are obtained from the specific patient, modified genetically ex vivo, and possess the remarkable capability to identify and eradicate targeted cancer cells. These modified cells are subsequently reintroduced into the patient, effectively treating blood cancer. CAR-T therapy is approved to be applied in leukemia due to its great clinical therapeutic effect on B cell hematological malignancies. However, solid tumors are more resistant to this therapy for many reasons. The abnormal vascular structure of solid tumors hampers CAR-T cell trafficking. Various kinds of immunosuppressive cells and chemicals in the tumor microenvironment (TME) accelerates CAR-T cell exhaustion, showing poor persistence in vivo. More and more researches have demonstrated that T cell fate is strongly associated with epigenetic regulation. Epigenetic modification is not a direct addition or deletion of DNA, but a reversible method including modifications on DNA and histones, and non-coding RNA (ncRNA)-mediated regulations. The change of epigenetic landscape in CAR-T cells largely determines the therapeutic performance in vivo. This research outlines three major barriers in CAR-T therapy, including T cell exhaustion, differentiation and infiltration. Additionally, the research elucidates several promising epigenetic reprogramming strategies to reduce CAR-T cells exhaustion, modulate the cell differentiation process, and enhance their infiltration into solid tumors.