Since the first CAR T therapy won approval in 2017, these engineered immune cells have transformed treatment for several blood cancers. However, despite promising responses in many patients, CAR T remains unpredictable. Some patients experience severe cytokine release syndrome (CRS) or neurotoxicity, while others tolerate treatment well. Likewise, the extent to which CAR T cells expand after infusion, a key driver of therapeutic success, varies widely between individuals.
In a study published in Science Immunology, investigators analyzed whole-genome sequencing data from patients enrolled in Kite Pharma's pivotal ZUMA-1 and ZUMA-7 clinical trials of axicabtagene ciloleucel (axi-cel), marketed as Yescarta. Their findings suggest that inherited genetic variants can shape both the safety and performance of CAR T therapy, offering new ways to predict toxicity and engineer improved cell therapies.
Unlike conventional drugs, autologous CAR T therapies are manufactured from each patient's own T cells, meaning inherent differences in T cell biology can influence both manufacturing and clinical outcomes. Understanding the genetic factors that shape T cell function could help researchers develop CAR T therapies that are safer, more consistent, and more effective.
Looking to inherited immune disorders for clues
The researchers first focused on genes linked to hemophagocytic lymphohistiocytosis (HLH), a rare inherited inflammatory disorder. HLH shares several clinical features with CRS, one of CAR T therapy's most serious complications, making these genes a logical starting point for investigating why some patients experience excessive immune activation.
One candidate stood out. Six patients in the ZUMA-1 trial carried damaging variants in STXBP2 (syntaxin binding protein 2), a gene involved in immune cell degranulation. Every one of these patients developed significant treatment-related toxicity following CAR T infusion.
Laboratory experiments helped explain why. T cells carrying defective STXBP2 showed impaired degranulation alongside increased production of inflammatory cytokines, suggesting that disrupted immune regulation may contribute to the inflammatory cascade responsible for CRS and neurotoxicity.
However, the association was not replicated in the ZUMA-7 trial. The authors suggested this difference may reflect variations in baseline patient characteristics, disease burden, prior treatments and toxicity management practices between the studies. Patients in ZUMA-1 generally had more advanced disease and had received more previous therapies, potentially creating a more inflammatory environment in which the effects of STXBP2 variants became more apparent.
Genes associated with CAR T enhancements
The team then broadened their search beyond HLH-associated genes and analyzed genetic variation across the entire genome. This unbiased screen identified variants in two genes, ADAMTSL3 and PTPN22, that correlated with improved protection against toxicity or enhanced CAR T cell expansion, respectively.
Patients carrying variants of ADAMTSL3 had lower levels of IL-15, a cytokine previously linked to CAR T-associated neurotoxicity. Although the exact mechanism is unclear, ADAMTSL3 is involved in regulating TGF-β (transforming growth factor-beta) signaling, a pathway that influences T-cell activation and function. Further studies will be needed to determine how these variants affect immune responses, but ADAMTSL3 represents a potential inherited marker of reduced CAR T toxicity.
Meanwhile, variants in PTPN22, a well-known negative regulator of T cell receptor signaling, were strongly associated with greater CAR T expansion after infusion in both ZUMA studies. Expansion is a key predictor of treatment efficacy, as engineered cells must proliferate rapidly within the patient to eliminate cancer cells. Although these variants were present in only around 5 percent of patients, carriers consistently showed the highest levels of CAR T expansion.
The finding suggests new engineering opportunities. Rather than simply using inherited variation as a biomarker, researchers may be able to intentionally disrupt PTPN22 during CAR T manufacturing using gene editing approaches such as CRISPR. Doing so could enhance expansion, reduce the number of cells required for treatment, and potentially help overcome T cell exhaustion, particularly in difficult-to-treat solid tumors.
More diverse datasets still needed
While the ZUMA studies provided an important proof of concept, differences in disease stage, prior treatments, ancestry, and treatment protocols may all influence how genetic variants affect CAR T cell behaviour. Before inherited genetic signatures can be translated into clinical decision-making or CAR T engineering strategies, researchers will need to validate these associations across larger and more diverse patient populations.
This question could become even more important as the field advances toward allogeneic or “off-the-shelf" CAR T therapies manufactured from healthy donors. If donor genetics influence CAR T cell function, genetic profiling could help identify donors whose cells are more likely to generate consistent, effective products.
Rather than viewing inherited variation solely as a source of patient-to-patient differences, studies like this suggest the genome could become a blueprint for designing next-generation cell therapies. The same genetic insights that reveal why some patients experience toxicity may ultimately help researchers build CAR T cells that are safer, more durable, and more effective.
