Chimeric antigen receptor (CAR)-redirected T cells: is there a place for them in infectious diseases?

The use of T cell–based adoptive immunotherapeutic strategies is emerging as an attractive alternative to currently used antiinfectious protocols in at-risk patients, such as those undergoing hematopoietic stem cells transplantation [1]. As more extensively tested in oncologic patients, two main strategies may be used: firstly, the infusion of autologous or donorderived total or pathogen-specific T cells, and secondly, the use of pathogen-specific engineered T cells. In the latest approach, it is included the redirection of T cells by using the so-called chimeric antigen receptors (CARs). CARs were firstly described in the late 1980s [2], and after design and technical improvements have recently reached the clinics with several ongoing clinical trials. In 2013, they were considered by Science magazine as important turning points in cancer immunotherapy—the major scientific breakthrough of that year [3]. In brief, CARs are artificial receptors constituted by a specific antigen-binding domain (usually, but not necessarily, represented by a single chain antibody fragment—scFv), an extracellular hinge region, a transmembrane domain, and a T cell receptor–derived intracellular signaling domain capable of triggering T cell activation [4]. This construct is used to transduce T cells which can therefore acquire a definite antigen specificity. Put simply, CARs may be considered as featuring the binding specificity of a monoclonal antibody (mAb) associated with the effector functions of a T cell. The main potential advantages of CARs are related to their capacity of recognizing antigens in a major histocompatibility complex (MHC)-independent manner, making them attractive immunotherapeutic tools. Ideally, the same CAR construct may be used effectively in different MHC-unrelated patients, one of the main limitations in the actual use of T cell–based therapy. Another important potential advantage is the capability of bypassing escape mechanisms based on MHC down-regulation, which may be put in practice by both neoplastic cells and infectious agents [5,6]. On the other hand, the lack of MHC control in T cell activation is the main theoretical risk