Adoptive immunotherapy for acute leukemia: New insights in chimeric antigen receptors

Abstract

Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells (LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despite the introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90’s, chimeric antigen receptors (CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding “living drug” specifically targeting the tumor-associated antigen, and ensure long-term anti-tumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.

Keywords: Chimeric antigen receptors; Adoptive immunotherapy; Acute leukemia; T cells; Immune surveillance

Core tip: Leukemia cells ultimately escape to the immune system, due to various mechanisms such as limited availability of tumor specific T cells or down-regulation in major histocompatibility complex expression. Chimeric antigen receptor (CAR) T cell technology redirects immune reactivity towards a broad variety of chosen antigens in a human leukocyte antigen-independent manner. Recent introduction of co-stimulatory domains in the CAR construct enhances significantly in vitro and in vivo expansion and persistence of these genetically modified T cells. First clinical trials, especially with anti-CD19 CAR T cells, report promising results in acute lymphoblastic leukemia.