Antigenic cells augment CAR T cells

Innovations in chimeric antigen receptor (CAR) T-cell immunotherapies are at the forefront of new treatments for HIV infections. In this issue of Blood, Rust et al describe new innovations in CAR T-cell immunotherapy to treat HIV that led to profound expansion and improved function of CAR T cells in vivo.¹ 

HIV causes a chronic lifelong infection in humans that the immune system is only partially able to control. Antiretroviral drugs have been developed that effectively suppress viral replication, but they are not a cure and can cause adverse effects and, in some instances, the virus can mutate to evade antiretroviral drugs. As an alternative to or augmentation of current antiretroviral drug therapies, cellular therapies, including CAR T-cell therapies, are being developed to suppress HIV replication.^2-4  The goal of HIV CAR T-cell immunotherapies is to promote the sustained remission of HIV infection without the need for antiretroviral drugs.

One problem that needs to be overcome in the HIV CAR T-cell field, is the establishment of methods that allow CAR T cells to replicate and persist. A confounding factor for CAR T-cell therapies for HIV is that there is very little HIV antigen available in individuals who are taking antiretroviral drugs⁵  to stimulate the production and maintenance of CAR T cells. To overcome this obstacle, Rust et al tested the hypothesis that infusion of antigen-expressing cells could trigger the CAR T cells in vivo to expand and persist (see figure). They tested this hypothesis in a simian/HIV (SHIV)-infected rhesus macaque model of HIV in which animals were treated with antiretroviral therapy to suppress viral replication and infused with autologous HIV envelope (Env)–targeting CAR T cells. They found that after the infusion of HIV Env-specific CAR T cells, the infusion of antigen-expressing cells (irradiated Env-expressing cells) led to the expansion of the CAR T cells. In addition, after stopping antiretroviral therapy, the CAR T cells further expanded to remarkable unprecedented levels. These cells, while declining over time, persisted and remained detectable for months after infusion. Importantly, this treatment was associated with a delay in viral rebound after antiretroviral drug therapy was stopped and was associated with ongoing control of viremia in a subset of treated animals.

Another problem that can have an impact on CAR T-cell immunotherapies is the exhaustion and loss of function of T cells.⁶  The exhaustion and loss of function of T cells can, in some instances, be reversed in vivo with treatments that block the programmed cell death protein 1 (PD-1) pathway.^7,8  As part of their treatment strategy, Rust et al administered an anti–PD-1 checkpoint inhibitor to address CAR T-cell exhaustion in a subset of treated animals. Treatment with anti–PD-1 triggered expansion of exhausted CAR T cells and, at the same time, it temporarily lowered viral loads to undetectable levels.

These exciting findings provide proof of principle that infusion of antigen-expressing cells in vivo can augment CAR T-cell responses for the successful engraftment and persistence of CAR T cells in tissues. These studies also support PD-1 blockade as an effective tool to put in the toolbox for developing HIV CAR T-cell immunotherapies. In sum, these important studies advance the HIV immunotherapy field toward the ultimate goal of curing HIV infections.