Broadly Applicable Approach Improves Persistence of CAR-T Cells

A research team from Albert Einstein College of Medicine has created a new manufacturing approach that, compared to the existing process, generates longer-lasting immune cells that provide more sustained control of human blood cancers and suppression of HIV-infection in mouse models.

CAR-T therapy reprograms a patient's T cells into targeted killers against cancer or infected cells, often achieving early successes. However, their effectiveness fades over time, with cancer recurring in roughly half of cases as activity declines. For HIV patients, while antiretroviral drugs suppress the virus, they cannot eradicate dormant reservoirs in long-lived immune cells, requiring lifelong medication and its associated side effects.

“Our goal was to engineer therapeutic immune cells so they would not only be powerful killers but also long-lived and capable of self-renewal, to markedly extend their effectiveness after infusion into patients,” stated Harris Goldstein, senior author of the study published in Science Advances. “By improving how we generate CAR-T cells, a treatment that acts as a ‘living drug,’ we would prolong their functional activity and prevent disease relapse after their potency wanes.” 

First author Erin Cole and colleagues developed HCW9206, a protein scaffold fusing three cytokines—IL-7, IL-15, and IL-21—that support T cell survival and memory formation. This replaced conventional activation, producing CAR-T cells where more than half were T memory stem cells, capable of self-renewal and generating ongoing waves of active fighters. Traditional methods yield under 5% of these rare, persistent cells.

“T memory stem cells are considered to be critical for long-term immune persistence,” Goldstein explained. “They can continually replenish the pool of active CAR-T cells, a crucially important attribute for their long-term success in combating both cancer and HIV infection.”

In leukemia mouse models, both cell types cleared initial tumors, but only scaffold-generated CAR-T cells mounted a robust recall response weeks later, blocking reintroduced cancer growth. Against HIV in humanized mice, these cells destroyed far more infected cells, including those from actual patients, demonstrating heightened antiviral power.

The results suggest potential to cut cancer relapses and foster drug-free HIV remission. “Now that we have shown that we can generate potent CAR-T cells that are longer-lived, we may be able to reduce blood cancer relapse rates and improve long-term remission for cancer patients,” Goldstein noted. “For HIV, immune cells with this kind of staying power may one day help maintain viral control after stopping antiretroviral therapy, a critical step toward sustained drug-free remission and, potentially, a functional cure.”