Germline genetics impact the safety and efficacy of engineered chimeric antigen receptor (CAR) T-cell therapies in patients with hematologic malignancies, according to study findings published in Science Immunology.
“These findings have important implications for understanding how CAR T cells behave in patients since each CAR T-cell product is unique to the person from whom it is manufactured, unlike all prior forms of therapy, which are identical across patients,” said lead author Mark B. Leick, MD, an oncologist at the Mass General Brigham Cancer Institute.
The study authors suggested that the results of the study could impact future CAR T-cell product design and patient management.
Study Methods
Researchers integrated whole germline sequencing from patients with lymphoma who were treated with axicabtagene ciloleucel from the ZUMA-1 and ZUMA-7 trials. They conducted detailed biomarker and functional analyses to identify potential germline variants that may influence clinical toxicity and pharmacokinetics.
Key Findings
The researchers found that putative deleterious variants in STXBP2 were enriched in patients who demonstrated toxicity from axicabtagene ciloleucel in the ZUMA-1 trial, but the findings were not confirmed among patients from the ZUMA-7 trial.
STXBP2-deficient or variant-expressing T cells induced more inflammatory cytokine production and macrophage activation, while variants in ADAMTSL3 were associated with protection from toxicity in both study groups. Variants in PTPN22 were associated with greater CAR T-cell expansion, leading to efficacy.
“This may have implications for identifying the right donor for CAR T cells, where a single donor can provide T cells for hundreds of patients, and for the design of augmented CAR T cells, based on a deeper understanding of how human genetic variation impacts CAR T-cell behavior,” said co-senior author Marcela Maus, MD, PhD, the Paula J. O'Keeffe Endowed Chair of the Mass General Brigham Cancer Institute and the Director of the Cellular Immunotherapy Program.
DISCLOSURES: This study was funded by Kite Pharma. For full disclosures of the study authors, visit science.org.
