CAR-T cell therapies represent one of the most significant innovations in recent years in the treatment of certain blood cancers. They are an advanced form of personalised immunotherapy in which a patient’s own peripheral blood immune cells, including T cells, key components of the immune system, are collected, genetically engineered in the laboratory to recognise proteins highly expressed by tumor cells, and then reinfused into the patient to target and eliminate the cancer. Despite the clinical outcomes achieved so far, patient responses are not always optimal or durable: the infused cells may fail to expand sufficiently or may not remain active over time.

A new study published in Cell proposes an evolution of this strategy, introducing a next-generation platform designed to generate CAR T cells enriched in stem-cell memory T (T_SCM) cells, a specific T-cell subset with enhanced potential to expand and persist in the long term. The results show, for the first time in a clinical trial, that CAR T cells based on this approach can induce complete remissions at very low doses and without lymphodepleting chemotherapy, typically administered before infusion to enhance treatment efficacy, while also exhibiting a favorable safety profile.

This first-in-human study was conducted by an international team led by Luca Gattinoni of the Leibniz Institute for Immunotherapy (LIT), who is also the first author of the study, together with James N. Kochenderfer of the National Cancer Institute (NCI) in Bethesda as co-corresponding author. The Humanitas Research Hospital, through the group led by Enrico Lugli – Head of the Laboratory of Translational Immunology, made a significant contribution to patient immunomonitoring, that is the longitudinal analysis of infused cells, using advanced technologies such as multidimensional flow cytometry and advanced bioinformatics to accurately track their presence and persistence in the body.

The strategy based on T_SCM cells originates from basic research conducted over a decade ago by Gattinoni and Lugli, who led to the discovery of this T-cell subset in humans and its potential application in immunotherapy.

Study Results: Clinical Evidence and Biological Profile of CAR T_SCM

T_SCM cells are a rare subset of immune cells with unique properties: they can self-renew, persist long term, and generate a strong anti-tumor response. By using them to produce more homogeneous CAR T-cell products, researchers observed that these cells expand more efficiently in the body and persist longer compared to conventional CAR T cells. This made it possible to achieve complete remissions even with very low cell doses. “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,” says Prof. Luca Gattinoni. It is important to note that similar commercial products are typically administered at doses on the order of approximately 2 million cells per kilogram and always in combination with preparative lymphodepletion, whereas such low doses, in the absence of conditioning, are generally ineffective, as observed in the standard cohort of this study.

Another key finding concerns the possibility of avoiding lymphodepleting chemotherapy, which is typically given before treatment to “make space” for CAR T cells and facilitate their expansion. Despite the absence of this step, CAR T_SCM cells were still able to expand effectively and reach high levels in the blood – a factor considered one of the strongest predictors of clinical efficacy.

How do CAR T_SCM cells behave in the body?

CAR T_SCM cells also demonstrated a favorable safety profile. “We also observed less cytokine-release syndrome on this study compared to most other CAR clinical trials that I have participated in,” notes Dr. James N. Kochenderfer. Cytokine release syndrome (CRS) is a common and potentially serious inflammatory reaction triggered when CAR T cells become active in the body. Remarkably, even at expansion levels that in conventional CAR T therapies are associated with severe CRS, patients treated with T_SCM cells experienced only mild side effects, suggesting that the T_SCM cell product may separate the beneficial effects of expansion from its toxic consequences.

Immunomonitoring conducted and coordinated by researchers at LIT in collaboration with scientists from Humanitas Research Hospital also provided deeper insight into how these cells behave over time. Unlike conventional CAR-T cells, CAR-T_SCM cells are not activated all at once; instead, they are recruited over time in successive small waves, maintaining a reservoir of “stem-like” cells capable of sustaining the anti-tumor response. In contrast to standard CAR-T cells, which tend to lose self-renewal capacity more rapidly, this mechanism may explain the greater expansion and persistence observed. “Rather than differentiating all at once, T_SCM cells are recruited in small, sequential waves — each cohort of active clones succeeding the last while preserving the long-term reservoir of quiescent stem-like cells. For the first time, we are witnessing this fundamental biology play out directly in patients,” explains Dr. Enrico Lugli.

New perspectives for CAR-T therapies

Overall, the study suggests that this approach could make CAR-T cell therapies more effective and tolerable, even at lower doses and with reduced reliance on lymphodepleting chemotherapy. Although these results will need to be confirmed in larger studies, they indicate that using a more homogeneous, stem-like T-cell population such as T_SCM cells could improve existing treatments and enhance the quality of clinical responses. The biological principles observed may also extend beyond the blood cancers studied here, potentially informing other CAR T applications and, in the future, solid tumors, where limited T-cell persistence remains one of the major challenges.