For years, chimeric antigen receptor T cells — better known as CAR-T cells — have been heralded as a revolutionary form of “living drug.” By reprogramming a patient’s own immune cells to seek out and destroy cancer or virus-infected cells, CAR-T therapy can achieve remarkable initial remissions.
Since the FDA approved tisagenlecleucel (Kymriah) in 2017 for the treatment of B-cell acute lymphoblastic leukemia, a total of seven CAR-T products — each targeting hematologic malignancies — have received FDA approval. These therapies have demonstrated remarkable clinical outcomes, including remission rates exceeding 80 percent in some cases.
However, these engineered immune cells often lose their potency over time. In roughly half of patients treated for certain blood cancers, the disease eventually returns once CAR-T activity wanes. The same challenge applies to HIV, where long-lived, latently infected cells can reignite infection if antiretroviral therapy or immune control is lost.
Now, a team led by scientists at the Albert Einstein College of Medicine may have found a way to address this obstacle. Their new approach, described in a paper published in Science Advances, uses a specially engineered multi-cytokine scaffold to generate CAR-T cells that survive longer, maintain their disease-fighting abilities, and self-renew over time. In mouse models of leukemia and HIV infection, these next-generation CAR-T cells not only eliminated diseased cells but also mounted strong “recall” responses weeks later, effectively preventing relapse.
“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,” Harris Goldstein, senior author and immunologist at Einstein, said in the press release. “By improving how we generate CAR-T cells, we would prolong their functional activity and prevent disease relapse after their potency wanes.”
A multi-cytokine scaffold
Cytokines function as the jet fuel that can amplify the activity of T cells. We were looking for the best combination of cytokine to use, like the best mix of jet fuel.
—Harris Goldstein, Albert Einstein College of Medicine
Goldstein and his team developed an alternative method for generating CAR-T cells using a protein scaffold called HCW9206. This scaffold links three naturally occurring cytokines — IL-7, IL-15, and IL-21 — that are known to promote T cell survival and immune memory.
“We have been looking at ways to harness and turbocharge the T cells in the immune system to treat HIV as well as cancer,” Goldstein told DDN. “Cytokines function as the jet fuel that can amplify the activity of T cells. We were looking for the best combination of cytokine to use, like the best mix of jet fuel.”
When the team used the multi-cytokine scaffold to activate T cells, more than half of the CAR-T cells exhibited characteristics of T memory stem cells, a rare population of long-lived cells capable of self-renewal and of generating new waves of active immune cells. By contrast, conventional CAR-T production methods produced fewer than five percent of these stem cell-like T cells.
T cells exist along a spectrum of maturation shaped by their environment. At one end are T memory stem cells, which have limited immediate killing ability but a strong capacity to self-renew. As T cells mature, they gain greater functional activity but gradually lose their ability to regenerate, becoming short-lived effector cells. Over time, these effector cells lose their activity and cannot replenish themselves.
“The differentiation state of the T cells is mediated by the expression of different genes,” Goldstein said. “We showed that HCW9206 induces the CAR-T cells to express the genes associated with the long-lived T memory stem cells with high regenerative capacity. It functions like the fountain of youth for T cells.”
The team tested their approach in mouse models of both leukemia and HIV infection. In the leukemia model, both conventional and multi-cytokine scaffold-generated CAR-T cells successfully eliminated cancer initially. However, when researchers simulated disease relapse by reintroducing leukemia cells, only the scaffold-generated CAR-T cells mounted a strong recall response.
“In the leukemia model, we were surprised to see that after rechallenge with the human leukemia cells, only mice treated with the HCW9206-generated CAR-T cells did not experience relapse, and this was associated with in vivo expansion of the anti-leukemia human CAR-T cells,” said Goldstein.
In a humanized mouse model of HIV infection, the multi-cytokine scaffold-generated CAR-T cells also demonstrated superior antiviral activity. They eliminated significantly more HIV-infected cells than conventionally manufactured CAR-T cells. Furthermore, when CAR-T cells were generated from patients living with HIV using this new method, they successfully eradicated HIV-infected cells, pointing toward the potential for long-term viral control.
These findings suggest that the new manufacturing approach could reduce relapse rates for blood cancers and improve long-term remission. For HIV, it raises the possibility of maintaining viral suppression without continuous antiretroviral therapy — a critical step toward sustained drug-free remission and potentially a functional cure.
Looking ahead
Memory T cells are known to persist for years or even decades. The key question is whether these engineered CAR-T cells can do the same in patients. Goldstein noted that previous studies have shown patients with the best outcomes often have CAR-T cells with a less differentiated, early memory phenotype, particularly T memory stem cells.
By simultaneously enhancing potency and persistence, this new approach addresses a major limitation that has historically constrained CAR-T therapy’s long-term effectiveness. The multi-cytokine scaffold doesn’t just remove the initial cancer, it primes the CAR-T cells to maintain functional activity over time, potentially reducing relapse rates and extending remission periods.
Moreover, the strategy could have broad applications beyond blood cancers. This platform may be adaptable to other immune cell therapies, opening doors for new approaches in oncology, infectious diseases, and potentially even chronic viral infections.
