The first clinical use of chimeric antigen receptor (CAR)-modified T cells was in HIV infection. In this setting, the CAR was composed of the receptor for the HIV envelope protein, namely the extracellular and transmembrane portions of the CD4 protein, fused to the T cell receptor (TCR)-ζ signaling molecule (CD4z CAR). The proposed mechanism of action was for transduced T cells to lyse HIV envelope–expressing T cells. Between 1998 and 2005, three clinical studies evaluated the CD4z CAR expressed in autologous CD4+ and CD8+ T cells via a retroviral vector in subjects with active viremia or in T cell–reconstituted patients with chronic HIV-1 infection. These studies showed that infusion of redirected T cells was feasible and safe; in addition, T cells trafficked to reservoirs of infection (mucosa) and had modest effects on viremia. A decade later, analysis of the data collected from these protocols in a long-term follow-up study demonstrated the safety of retroviral modification of human T cells and the long-term persistence of CAR-modified T cells, with an estimated half-life greater than 16 years. This study added to the literature indicating that T cells were less susceptible to retrovirus-mediated insertional mutagenesis than were hematopoietic stem cells (HSCs). In 2009, the remarkable story of the "Berlin patient" was published; this was the first report of a patient being functionally cured of HIV infection following an allogeneic HSC transplant for acute myelogenous leukemia.The donor was homozygous for the CCR5 32 mutation, which confers genetic resistance to HIV infection. The findings from this report have challenged the field to develop cell therapy–based approaches that do not require myeloablative chemotherapy or allogeneic donors. One such approach has been to develop gene therapy strategies to reduce CCR5 expression, either through shRNA encoded by lentiviral vectors or through gene-editing strategies using zinc-finger nucleases (ZFNs) to disrupt the CCR5 gene in T cells. In these cases, autologous gene modified T cells are reinfused with the goal of reconstituting the T cell repertoire in HIV-infected patients. Interpretation of T cell effects on viremia and control of HIV may be affected by ongoing treatment with highly active antiretroviral therapy (HAART), and carefully designed trials with scheduled, thoroughly monitored treatment interruptions are under way.
Patients with hematologic malignancy undergoing allogeneic bone marrow transplantation are also at high risk for viral illness, particularly from reactivation of chronic viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6; primary adenovirus infection can also cause acute and severe illness in this immunocompromised population. Although pharmacologic treatments for these viruses are available, they often have limited efficacy, must be administered recursively, and have significant side effects. For these reasons, several transplant centers have focused on developing donor-derived virus-specificT cells that can be administered as a donor lymphocyte infusion (DLI), either prophylactically or as treatment. Because of the limitations in approaching healthy donors and single-patient manufacturing lots of virus-specific T cells, some centers have developed "third-party" T cell banks derived from a panel of donors selected to span the most common HLA alleles. The Baylor group has pioneered the use of T cell lines that are specific for three to five viruses simultaneously and has administered these to patients either as donor-derived or as third-party-derived lymphocyte infusions. Importantly, the incidence and severity of graft-versus-host disease (GvHD) have been limited or tolerable in all these studies. These forms of adoptive immunotherapy are the most clinically advanced, with publication of phase II, multicenter trials.
Maus MV et al. Adoptive Immunotherapy for Cancer or Viruses. Annual review of immunology. 2014;32:189-225.