Summary
An analysis of 783 patients with lymphoma linked a higher proportion of naive-like T cells in CAR T products to longer progression-free survival. The association was also found in an independent validation cohort.
A multicenter analysis published in Nature Medicine linked a higher proportion of naive-like T cells in CAR T products to longer progression-free survival (PFS) among patients treated for non-Hodgkin lymphoma. The study analysed 580 patients who received axicabtagene ciloleucel (axi-cel) and tested the finding in a separate cohort of 203 patients treated with axi-cel-based therapy or brexucabtagene autoleucel (brexu-cel).
The researchers found that the cell profile was associated with PFS even after statistical adjustment for clinical features and CAR T-cell expansion. The result identifies a product characteristic that may help guide research into how CAR T cells are manufactured; it does not show that deliberately changing that characteristic improves outcomes.
A cell phenotype associated with longer progression-free survival
CAR T-cell therapy uses a patient’s own T cells, modified to recognise a target such as CD19 on B cells, and infused back into the patient. The study examined the proportion of cells in the infused product that expressed both CCR7 and CD45RA. These markers identify a less differentiated population, described by the authors as naive-like T cells. Because stem-cell-memory T cells can also express these markers, the researchers used the more cautious term rather than treating the measurement as a definitive count of that specific cell type.
In the main cohort, the median follow-up was 41.9 months. Patients in the high group—those above the 75th percentile for naive-like T-cell proportion, a cutoff of 37.7%—had a lower rate of progression or death than those in the low group, whose proportion was at or below the 25th percentile (12.2%). The study reported a hazard ratio of 0.46 for high versus low, with a 95% confidence interval of 0.31–0.68. In this analysis, that corresponds to a 54% lower hazard of progression or death for the high group; it is not an estimate of an individual patient’s absolute chance of benefit.
The association appeared to reflect both response and its durability: ongoing response rates were about twice as high in the high group as in the low group. A separate validation cohort of 203 patients, followed for a median of 27 months, showed a similar association. Across the two cohorts, the analysis included 783 patients.
The proportion of naive-like cells also remained associated with PFS in models that accounted for measured disease and patient characteristics, including tumour burden, inflammation markers and CAR T-cell expansion. In a subset of 112 patients with tumour measurements, the product-cell association persisted after accounting for features of the tumour microenvironment. The researchers also found no association between the proportion of these cells and the severity of cytokine release syndrome or neurotoxicity in either cohort.
What the findings mean for CAR T design
The cell profile may provide a useful focus for studies seeking to improve CAR T products. In a deeper analysis of 116 products, the CD8 T-cell cluster associated with improved PFS expressed markers of a less differentiated state and had low or absent expression of the exhaustion markers PD-1, LAG-3 and TIGIT. This supports the idea that the CCR7-positive, CD45RA-positive measurement captures features of a less differentiated T-cell population, though it does not settle the precise identity or mechanism of the cells.
The proportion of naive-like cells was inversely associated with the number of prior treatment lines. That relationship was seen in both the product and matched apheresis samples, suggesting that treatment history and the manufacturing process may be relevant to the final cell composition. The study’s authors propose that approaches to preserve or enrich less differentiated cells merit further investigation.
The evidence is an analysis of cell products and outcomes from clinical-trial cohorts, not a randomized comparison of products deliberately made with different proportions of naive-like cells. The findings therefore establish an association, rather than showing that increasing this cell population would itself extend survival. The main analysis focused on CD28-based CAR T products in lymphoma, and the authors note that the marker combination cannot definitively distinguish naive cells from stem-cell-memory cells. Further work will be needed to identify the population responsible and test whether manufacturing changes can improve clinical outcomes.