Several key observations and discoveries foundational to the overall field of CAR T cell therapy were made during the clinical investigation of CD4-ζ CAR T cells. While clinical success was not achieved with these early efforts in the just-emerging CAR T cell field, these efforts were not a “failure,” but in fact, successfully laid fundamental groundwork that enabled success using CAR T cells to treat CD19-expressing tumors. These studies tested the ability of T cells expressing a major histocompatibility complex (MHC)-unrestricted chimeric receptor consisting of CD4, as the natural ligand of the HIV Envelope (Env) glycoprotein, and the CD3 zeta (ζ) chain ( 1) to suppress viral replication in HIV–infected individuals ( 2– 4). In the 1990s when antiretroviral therapy (ART) was in its infancy and not yet able to provide durable control of HIV replication, the rationale to treat HIV infection with CAR T cell therapy advanced more rapidly, and in this setting, the first CAR T cell trials were performed. Thus, the use of CARs to redirect T cells toward both HIV and cancer as a means to bolster T cell control of these maladies was an attractive concept, which led to the preclinical studies using both HIV and cancer models. How Initial HIV Studies Paved the way for Successful CD19-Directed CAR Therapyįrom a T cell perspective, controlling HIV replication and cancer growth share many of the same challenges: antigen escape, antigen persistence resulting in T cell exhaustion, and active mechanisms employed by both HIV and tumors to avoid T cell recognition and elimination. Additionally, the unique challenges that must be overcome to develop a successful HIV CAR T cell therapy will be highlighted. This mini review will focus on how early CAR T cell studies in HIV paved the way for cancer CAR T cell therapy and how progress in cancer CAR therapy has and will continue to be instructive for the development of HIV CAR T cell therapy.
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Many lessons have been learned on how to best engineer T cells to cure cancer, but not all of these lessons apply when developing CARs to treat and cure HIV.
Now there is great interest in revisiting the concept of using CAR-expressing T cells as part of a strategy to cure HIV. Re-directing T cells via chimeric antigen receptors (CARs) was first tested in HIV-infected individuals with limited success, but these pioneering studies laid the groundwork for the clinically successful CD19 CARs that were recently FDA approved.