A Genetic Signature May Predict Who Gets Sick From CAR T Cell Therapy

Germline genetic variants may help explain why CAR T cell therapy produces such variable toxicity across patients with aggressive lymphoma, according to findings published in Science Immunology.1 Investigators identified a specific gene, STXBP2, whose variants were enriched among patients who developed severe toxicity after treatment with axicabtagene ciloleucel.¹

"CAR T cells are different than every other form of therapy that came before," said Mark B. Leick, MD, medical oncologist and physician-scientist at Massachusetts General Hospital and the study's corresponding author. Unlike a standardized drug, Leick noted, CAR T cells are manufactured from a patient's own T cells, carrying all of that patient's inherited genetic variation into the final product.

A Rare Disease Pointed Investigators Toward STXBP2

Investigators performed whole genome sequencing on patients with aggressive lymphoma treated with axicabtagene ciloleucel in the ZUMA-1 (n = 86 evaluable) and ZUMA-7 (n = 150 evaluable) clinical trials, in partnership with Kite Pharma.1 The hypothesis was rooted in hemophagocytic lymphohistiocytosis (HLH), a rare inherited hyperinflammatory syndrome that shares key biochemical features with cytokine release syndrome (CRS), the most common toxicity of CAR T cell therapy.1 Leick and colleagues reasoned that milder, adult-onset forms of the same genetic defects that cause HLH might also be driving toxicity in some CAR T cell recipients.

Among the ZUMA-1 toxicity cohort (n = 39), 6 patients (15.4%; 95% CI, 5.9%-30.1%) carried putative deleterious variants in STXBP2, a gene involved in lymphocyte degranulation, compared with none in the 39-patient control cohort (OR, >1.44; nominal P = .025).1 The finding was not replicated in ZUMA-7, which investigators attributed to that cohort's lower baseline inflammation and fewer prior treatments relative to the more heavily pretreated ZUMA-1 population.¹

CRISPR Experiments Confirmed a Mechanistic Role

To confirm a mechanistic role for the gene, investigators used CRISPR-Cas9 to knock out STXBP2 in CAR T cells manufactured from healthy donors.¹ The STXBP2-deficient cells showed impaired degranulation and cytotoxicity, along with increased inflammatory cytokine production when cocultured with tumor targets, mirroring the cytokine profile seen in variant carriers in the clinical cohort.¹

Investigators noted that the ZUMA-1 and ZUMA-7 cohorts were predominantly of European ancestry, limiting conclusions in non-European populations, and that the number of STXBP2 variant carriers identified was small, warranting confirmation in larger, more diverse cohorts.¹

Editor’s Note: Leick reports relevant disclosures with BioNTech, Cabaletta Bio, and Adaptimmune.

References

1. Leick MB, Sun B, Birocchi F, et al. Genomic correlates of clinical CAR T cell activity. Sci Immunol. 2026;11(121). doi:10.1126/sciimmunol.aef4134

2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.