Researchers at UCLA have developed a new CAR T gene therapy that could potentially be used to treat HIV-1. The researchers demonstrated their method produced superior and longer lasting results in mouse models of the disease than other CAR therapies.
Chimeric antigen receptor (CAR) T-cell therapy has shown great promise in the treatment of cancer. CAR therapy is a type of immunotherapy that involves genetically modifying blood-forming stem cells to produce T cells that are capable of finding and destroying cancer cells. Researchers have tried to adapt this approach to treat HIV, the virus that causes AIDS.
While CAR therapy has shown promise for treating HIV-1, the most common form of the two types of HIV, previous CAR therapy techniques have not had a long-lasting effect. When malignant or infected cells appear months after treatment, they are no longer identified and killed by the modified T cells. A new form of CAR therapy was required to target HIV-1 infected cells that was also capable of suppressing viral reactivations from the long-lived latent reservoir.
The new approach developed by the UCLA researchers has shown potential not only for destroying HIV-1 infected cells, but also has created ‘memory cells’ that provide long lasting protection and may even provide protection for a lifetime.
Previously the researchers had demonstrated CAR therapy could be used to engineer blood-forming stem cells that carry chimeric antigen receptors that generate T cells capable of finding and destroying cells infected with HIV-1.
HIV-1 binds to CD4 molecules in order to infect cells. In the previous study, the researchers created a CAR molecule that contained part of the CD4 molecule and were able to hijack the infection process. HIV would bind to the CD4 section of the CAR molecule on the T cells, other parts of the CAR molecule would then activate the cell and kill the virus. However, the CAR molecule had two domains which still had potential to allow HIV infection.
The key to improving their technique was the removal of these domains. They used a truncated CD4 molecule for the gene therapy that lacked these domains, but had another domain that made the cells resistant to infection, resulting in a much longer lasting cell response to HIV.
The initial approach resulted in the continuous production of T cells capable of fighting HIV for at least 2 years, but those cells were only activated when they encountered HIV. The new approach changed the way the T cells respond, and instead of waiting to encounter HIV or parts of the virus to induce a response, the immune system became primed and ready to respond, in a similar way to a vaccine priming the immune system to kill a virus. The new approach also resulted in significant production of memory T cells that were capable of quickly responding to reactivated HIV.
“We found this latest generation of CARs successfully modified and allowed in vivo engraftment that resulted in the development of effective anti-HIV CAR T cells with robust memory formation and viral control,” explained the researchers. “Our study highlights the identification of a next-generation CAR molecule that protected cells from infection, targeted and reduced HIV burdens, and serves as an ideal developmental candidate for further clinical studies.”
You can read more about the study in the paper – Robust CAR-T memory formation and function via hematopoietic stem cell delivery – which was recently published in the journal PLOS Pathogens. DOI: 10.1371/journal.ppat.1009404