Rather than producing one type of chimeric antigen receptor (CAR) from a patient’s T cells, as is the case with currently available CAR-T treatments for blood cancers, a team of scientists is pursuing a new idea for using the technology to treat HIV. They've designed CAR-T cells with two CAR molecules, and they've charted promising results for the approach in mice.
A team of scientists from the Albert Einstein College of Medicine and the University of Pittsburgh worked with Lentigen—a biotech focused on designing lentiviral vectors for gene and cell therapy—to develop the HIV-targeting CAR-T cells, which they call “duoCAR-T cells.”
In a study published in the journal Science Translational Medicine, the researchers showed that the duoCAR-T could effectively kill immune cells infected with HIV in a humanized mouse model. They also suggested the approach might be able to reduce HIV "reservoirs," groups of dormant infected immune cells that can’t be targeted with traditional antiretroviral drugs.
Clinical trials of the approach are slated to begin in early 2020 at the University of California, San Francisco and later at the Jacobi Medical Center, which is affiliated with the Albert Einstein College of Medicine, Dropulić said in a video interview.
CAR-T cell therapies modify a patient’s T cells to produce a CAR structure on their surface that allows them to latch onto and kill cancer cells. The notion that a similar approach might work in HIV is based on the fact that the infection starts with the binding of HIV’s outer coat protein, called envelope glycoprotein, to the CD4 receptor on immune cells.
Previously scientists had made anti-HIV CARs that used the CD4 receptor as the targeting site to kill infected cells. However, they found that these CD4-based CARs rendered the engineered T cells susceptible to HIV infection. To overcome this, Boro Dropulić at Lentigen and colleagues designed duoCAR-T cells that target multiple sites on the HIV envelope glycoprotein.
The team developed over 40 HIV-based lentiviral vectors. The researchers found that the best candidate contained two CAR molecules that can target three particularly binding sites on the HIV coat. In the lab, the cell therapy eliminated up to 99% of immune cells infected with 11 different strains of HIV—including some treatment-resistant ones—and was more potent compared to conventional monoCAR-T cells, they discovered.
In the spleens of the humanized mice, the therapy suppressed HIV infection by 97% after seven days of treatment, significantly outperforming the 42% and 61% suppression rate posted by two monoCAR-T cells.
What’s more, the CAR-T cells themselves also resisted HIV infection after 30 days, while CD4 T cells in control mice were almost completely depleted by the virus, the team reported. The researchers suggested that the persistence of duoCAR-T cells could give them the power to suppress HIV over the long term.
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For the study, Dropulić and colleagues used C46 as a backbone of their CAR construct. A similar approach has been tried by scientists at the University of California, Los Angeles, who engineered blood-forming stem cells to carry a CAR that binds to HIV via CD4.
The holy grail of HIV research is a cure, but to get there, new therapies will need to be able to attack the HIV reservoir, where the virus bides its time until it's able to rebound. A Cornell University team recently showed that blocking a long noncoding RNA called SAF in HIV-infected cells could lead to reservoir self-destruction. Last year, scientists at the University of North Carolina at Chapel Hill made some progress with their method that involves growing a patient’s own T cells ex vivo and combining them with drugs that reveal reservoirs to the immune system.
Dropulić's team found that most of mice treated with the duoCAR-T cells had no detectable HIV DNA in their spleens, which the researchers believe signifies that the approach may be able to shrink HIV reservoirs by eliminating infected cells. They also suggested that combining duoCAR-T cells with the so-called shock and kill approach might offer a path toward functionally curing HIV. CAR-T cells could work with other agents to reactivate latent HIV so that the reservoirs can be eliminated, they argued.