Stem cell transplants from donors can cure certain blood cancers, but when relapse does occur, options are limited. A treatment known as donor lymphocyte infusion (DLI) is available; however, it is often ineffective for B-cell–derived leukemias and lymphomas. In addition, it can cause a serious complication called graft-versus-host disease (GvHD), in which the donor’s immune cells attack the patient’s own tissues.

CAR (Chimeric Antigen Receptor) T cells are immune cells that have been genetically engineered to recognize and destroy cancer cells. Scientists have been exploring whether using donor-derived CAR T cells specific for a B cell antigen could fight the cancer more specifically without causing GvHD. A key obstacle, though, has remained: without chemotherapy to prepare the body, infused CAR T cells often fail to survive, multiply, or last long enough to do the job.

Luca Gattinoni and James Kochendorfer, together with their international team, report a new potential solution. They show for the first time in humans that CAR T cells engineered to adopt a “stem-cell memory” identity — known as T_SCM cells — can induce complete cancer remissions at remarkably low doses, and without chemotherapy preconditioning.

T_SCM cells make up only a small part of the body’s T cell population, but they behave very differently from typical immune cells. They can renew themselves over extended periods, produce a wide range of cancer-fighting cells, and keep working against tumors for longer. Standard CAR T-cell therapies usually contain very few of these powerful cells. Gattinoni and colleagues first identified T_SCM cells in humans more than a decade ago (Gattinoni et al., Nature Medicine 2011) and later developed a way to reliably produce them in the lab. This study is the first to test this new approach in patients, resulting in a CAR T-cell therapy that is more consistent and well tolerated. “Today’s CAR T-cell products are heterogeneous, and that variability is reflected in the range of clinical responses and toxicity profiles we see in patients. To address this, we developed a highly homogeneous CD8+ CAR T-cell product selectively enriched for T_SCM cells and compared its performance to conventional CAR T cells,” explains Gabriele Inchingolo, a CRC TRR 221 PhD student in Gattinoni’s  team and co-first author of the study.

The early-stage clinical trial took place at the U.S. National Cancer Institute and involved patients whose B-cell cancers had come back after a stem cell transplant, a situation where treatment options are very limited. Patients were split into two groups: one received a standard CAR T-cell therapy, while the other received the new version enriched with T_SCM cells. Notably, patients did not receive chemotherapy beforehand, allowing researchers to clearly compare how the two cell products performed on their own.

The results were striking. On a per-cell basis, T_SCM-derived CAR T cells achieved higher levels in the bloodstream—a measure that, across many CAR T studies, strongly predicts clinical success. “Seeing patients achieve complete responses at doses as low as 250,000 cells per kilogram, without chemotherapy preconditioning, validates years of preclinical work and opens a new chapter in CAR T-cell design,” said Prof. Gattinoni.

Importantly, none of the patients developed GvHD. Side effects were also milder in the T_SCM group. While standard CAR T-cell treatments can trigger strong inflammatory reactions, patients receiving the T_SCM-enriched cells experienced only mild symptoms, even when the cells expanded to high levels. This suggests the new approach may separate strong anti-cancer effects from harmful side effects. “This is precisely the therapeutic window we have been trying to open — robust anti-tumor activity with a safety profile that does not compromise the patient,” says Dr. Dennis Harrer. “The absence of GvHD is striking, but what makes the T_SCM product truly distinctive is that even at expansion levels that caused severe toxic reactions with conventional CAR T cells, these cells remained remarkably well tolerated, suggesting the stem-like state changes how the immune response unfolds.”

Researchers also observed that the two treatments behaved differently over time. Standard CAR T cells tended to burn out as they multiplied, while the T_SCM cells kept a reserve of “younger” cells that could step in later. Instead of acting all at once, these cells worked in waves, potentially helping to sustain the anti-cancer response. “For the first time, we are witnessing this fundamental biology play out directly in patients,” said Enrico Lugli, PhD, from Humanitas Research Hospital, who helped lead the immune monitoring work.

In the few cases where the therapy was ineffective, the reasons proved informative. The authors found that the T cells themselves were not at fault; instead, external factors played a key role. These included low expression of the CD19 target on tumor cells, immunosuppressive signals—particularly the cytokine IL-10—and immune responses directed against the CAR construct. These insights offer a clear direction for the design of next-generation trials. The full potential of CAR T_SCM cells remains to be realized, and future studies that incorporate lymphodepleting preconditioning, fully humanized CAR constructs, and the inclusion of CD4+ T cells are anticipated to further improve outcomes. The biological principles identified here may extend beyond the post-transplant setting, with possible relevance to standard autologous CAR T-cell therapies and even solid tumors, where limited T-cell persistence has historically posed a challenge. “We have shown that a more defined, stem-like cell product can perform effectively at lower doses. By employing a highly homogeneous T_SCM population, we can potentially achieve more consistent engraftment and persistence, paving the way for more predictable outcomes and more rationally designed clinical trials,” concluded Gattinoni.

 

Read the full article:

https://www.cell.com/cell/fulltext/S0092-8674(26)00383-1

Photo – source NIH -: PET-images showing a complete response of Leukemia after CAR  T_SCM  therapy.