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Updated: Aug 6, 2026
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
Genomic correlates of clinical CAR T cell activity
Mark B Leick1,2,3,4, Baihe Sun4,5, Filippo Birocchi1,2,3
1Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Abstract:
Germline variants influence immune checkpoint inhibitor responses, but their role in engineered immune cell therapies, such as chimeric antigen receptor T cells (CAR T cells), remains unclear. We integrated whole germline sequencing from patients with lymphoma treated with axicabtagene ciloleucel CAR T cell products in the ZUMA-1 and ZUMA-7 clinical trials with detailed biomarker and functional analyses to identify variants influencing clinical toxicity and pharmacokinetics. Putative deleterious variants in STXBP2 (syntaxin binding protein 2) were enriched among patients with toxicity in ZUMA-1, although not confirmed in ZUMA-7. Mechanistically, STXBP2-deficient or variant-expressing T cells triggered increased inflammatory cytokine production and macrophage activation. Conversely, variants in ADAMTSL3, a TGFβ (transforming growth factor-β) signaling regulator, correlated with protection from toxicity across both trials. Furthermore, variants in PTPN22, a negative regulator of T cell receptor signaling, strongly associated with enhanced CAR T cell expansion, a key determinant of efficacy. Together, these findings demonstrate that germline genetics shape the safety and activity of engineered immune cell therapies, affecting future design and patient management.
Insights
Germline genetic variants impact chimeric antigen receptor T cell (CAR T cell) therapy safety and efficacy. Specific gene variants influence toxicity and CAR T cell expansion, guiding future treatment strategies.
Area of Science:
- Immunology
- Genetics
- Oncology
Background:
- Germline variants are known to affect responses to immune checkpoint inhibitors.
- The impact of germline genetics on engineered immune cell therapies like CAR T cells is not well understood.
Purpose of the Study:
- To investigate the role of germline genetic variants in the safety and efficacy of axicabtagene ciloleucel CAR T cell therapy.
- To identify specific variants influencing clinical toxicity and pharmacokinetics in lymphoma patients.
Main Methods:
- Integrated whole germline sequencing from ZUMA-1 and ZUMA-7 trial patients.
- Biomarker and functional analyses of identified variants.
- Correlation of variants with clinical toxicity, pharmacokinetics, and CAR T cell expansion.
Main Results:
- Enrichment of putative deleterious *STXBP2* variants in patients with toxicity in ZUMA-1, with mechanistic links to inflammation and macrophage activation.
- *ADAMTSL3* variants correlated with protection from toxicity across both trials.
- *PTPN22* variants strongly associated with enhanced CAR T cell expansion and efficacy.
Conclusions:
- Germline genetics significantly shape the safety and activity profiles of CAR T cell therapies.
- Identified variants in *STXBP2*, *ADAMTSL3*, and *PTPN22* provide insights into CAR T cell therapy mechanisms.
- Findings may inform future CAR T cell therapy design and patient selection for improved outcomes.
![Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F62334.jpg&w=3840&q=50)
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