Multi-cytokine scaffold helps CAR-T cells fight cancer and HIV for longer

A research team led by Albert Einstein College of Medicine scientists has developed a new strategy to engineer immune cells that dramatically prolongs their effectiveness after being infused into patients to fight cancer and HIV, addressing a major limitation of current treatments. Their findings, published in Science Advances, describe a 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.

“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,” said senior author Harris Goldstein, M.D., professor of pediatrics and of microbiology & immunology and director of the Einstein-Rockefeller-CUNY-Mount Sinai Center for AIDS Research.

“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.” Dr. Goldstein also holds the Charles Michael Chair in Autoimmune Diseases at Einstein.

The CAR-T durability challenge

To turbocharge disease-specific immune responses in patients, CAR-T cells are produced by removing a person’s immune T cells and inserting genes that reprogram them to act as guided missiles to recognize and selectively eliminate cancer cells or virus-infected cells.

After being generated in the laboratory, the engineered CAR-T cells are infused back into patients, where they seek out and eliminate the targeted malignant or infected cells. However, the long-term efficacy of this therapy has been limited by a major obstacle.

Although CAR-T therapy can initially produce dramatic remissions, their killing ability often diminishes over time. In roughly half of treated cancer patients, as the activity of the CAR-T cells dwindles, the cancer returns.

The same persistence problem has constrained efforts to extend CAR-T therapy to treat people living with HIV. Current antiretroviral drugs (ART) can suppress HIV production to undetectable levels but cannot eliminate immune cells already infected with HIV.

If this treatment is stopped, the virus hidden inside immune cells in long-lived, dormant HIV reservoirs reawakens to restore widespread infection. As a result, people living with HIV must take ART for life, which can lead to metabolic, neurological, cardiovascular, and other side effects.

Needed: A new way to make immune cells

To achieve a functional cure for cancer and HIV using CAR-T cells, the engineered cells would need to patrol the body for years, continually hunting down and eliminating residual malignant or infected cells, a level of long-term functional persistence not yet achievable using current manufacturing methods.

To overcome this drawback, Dr. Goldstein and colleagues, most notably Erin Cole, M.S., a graduate student in his laboratory and first author of the study, developed an alternative approach for producing CAR-T cells using a specially engineered protein scaffold called HCW9206.

This scaffold links three naturally occurring cytokines (immune cell signaling proteins)—IL-7, IL-15, and IL-21—which are known to promote T cell survival and immune memory. When the team used this multi-cytokine scaffold to generate CAR-T cells instead of the standard activation protocol, the results were striking.

The multi-cytokine scaffold produced CAR-T cells that retained strong disease-fighting abilities. Most importantly, more than half of these CAR-T cells belong to a rare population known as T memory stem cells, long-lived cells that are capable of self-renewal and of generating fresh waves of highly active immune fighters over time. By contrast, less than 5% of CAR-T cells produced using the conventional method displayed this long-lived, stem cell-like profile.

“T memory stem cells are considered to be critical for long-term immune persistence,” said Dr. Goldstein. “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.”

A more persistent response

In a mouse model of human leukemia, both conventional and multi-cytokine scaffold-generated CAR-T cells eliminated human cancer cells after the initial treatment.

But a few weeks later, when the researchers simulated cancer relapse by re-infusing these leukemia cells into the mice, only the multi-cytokine scaffold-engineered CAR-T cells mounted a strong “recall” response, expanding in number again and preventing tumor recurrence.

In a humanized mouse model of HIV infection, the multi-cytokine scaffold-generated CAR-T cells exhibited enhanced antiviral potency by eliminating significantly more HIV-infected cells than conventionally manufactured CAR-T cells. In addition, CAR-T cells generated from patients living with HIV using the new multi-cytokine scaffold production technique successfully eradicated HIV-infected cells.

The findings from this research could have important implications across the CAR-T cell field.

“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,” Dr. Goldstein said.

“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.”