Adding a second step to CAR T-cell therapy may make it effective against HIV

Chimeric antigen receptor or CAR T-cell therapy is FDA approved to treat patients with blood cancers including non-Hodgkins lymphoma and acute lymphoblastic leukemia, whose disease persists or returns following first-line treatments. One reason CAR T-cell therapy is effective is because a patient’s blood contains an abundance of the cancer cells that stimulate the activation and expansion of the modified T-cells. 

Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates.For people with HIV, however, it’s a different story. They do not have sufficient HIV-infected cells to trigger long-term expansion of CAR T-cells. Many are on antiretroviral therapy (ART) which is designed to suppress the virus, and any virus that does exist is not usually detectable in circulating blood, but rather is found in lymphoid tissues, the gut, and central nervous system.  

Frederick National Laboratory scientists and other colleagues led by investigators at the Fred Hutchinson Cancer Center have developed a manufacturing model to overcome the limitations posed by insufficient antigenic material for CAR T therapy. In a paper published in Blood, lead author Christopher Peterson from Fred Hutchinson indicates it is the first preclinical study—in an animal model--to show expansion of virus-specific CAR T-cells in infected hosts on ART that ultimately delayed the return of the virus when ART was discontinued. 

In addition, results of the study show the CAR T-cell therapy was safe for the subjects in their experiments, and the authors said that bodes well for an ongoing clinical trial of CD4 CAR T-cells in HIV-infected people who are stable on ART.   

CAR-T for virus calls for different approach 

This small study looked at four rhesus macaques infected with SHIV, a laboratory-engineered virus designed to cause AIDS disease in monkeys and allow testing of HIV-specific treatments. The animals were on ART for about 18 months.  

CAR T-cell therapy for leukemia in humans takes some of the patient’s own healthy cells and modifies them in the lab to boost the body’s immune response when they are injected back into the patient and expand to attack the cancer.  

In this study, CD4 T cells were removed from each animal and sent to the laboratory for modification in preparation for CAR-T therapy, roughly an eight-day process. The animals then received an infusion of their own modified CD4 CAR-T cells to help fight HIV infection. 

The animals received a second infusion of a specific line of laboratory-grown cells, modified to express HIV viral proteins. This supplemental round of cells was infused 19 days after the initial infusion and was designed to boost the expansion of the infused, anti-viral CAR T-cells. 

Second round of cell therapy appears to boost effectiveness 

ART was withdrawn from the animals 12 days after the boost. Researchers said blood tests showed the CD4 CAR T-cells successfully expanded in all four of the animals. Two of the four experienced cell expansion even before ART was removed. There was also evidence of cell expansion in tissue samples from the gut, lymph nodes, and other locations in the body where HIV is known to persist even when a patient is on ART. Results also showed the CD4 CAR T-cell treated animals experienced a slower rebound of the virus upon ART discontinuation compared to those that did not undergo CAR T-cell therapy. These results were not statistically significant and did not persist in two of the four monkeys. 

“The results of this study show HIV/SHIV-specific CAR T-cells can expand in the blood and lymphoid tissues following a boost with HIV envelope-expressing cells,” said FNL’s Christine Fennessey, who along with AIDS and Cancer Virus Program colleague Brandon Keele was co-author on the study.  “This finding lays the groundwork for similar two-step therapies for other CAR T-cell targets with limited antigen expression, such as solid cancerous tumors.”